Article | Published:

Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits

Nature Genetics volume 48, pages 867876 (2016) | Download Citation

Abstract

Hematologic measures such as hematocrit and white blood cell (WBC) count are heritable and clinically relevant. We analyzed erythrocyte and WBC phenotypes in 52,531 individuals (37,775 of European ancestry, 11,589 African Americans, and 3,167 Hispanic Americans) from 16 population-based cohorts with Illumina HumanExome BeadChip genotypes. We then performed replication analyses of new discoveries in 18,018 European-American women and 5,261 Han Chinese. We identified and replicated four new erythrocyte trait–locus associations (CEP89, SHROOM3, FADS2, and APOE) and six new WBC loci for neutrophil count (S1PR4), monocyte count (BTBD8, NLRP12, and IL17RA), eosinophil count (IRF1), and total WBC count (MYB). The association of a rare missense variant in S1PR4 supports the role of sphingosine-1-phosphate signaling in leukocyte trafficking and circulating neutrophil counts. Loss-of-function experiments for S1pr4 in mouse and s1pr4 in zebrafish demonstrated phenotypes consistent with the association observed in humans and altered kinetics of neutrophil recruitment and resolution in response to tissue injury.

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Acknowledgements

We thank the staff and participants of all studies for their important contributions. A complete list of acknowledgments for each study is available in the Supplementary Note.

This work was supported by the following grants and contracts: US National Institutes of Health contracts (N01AG12100, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC25195, N02HL64278, N01AG62101, N01AG62103, N01AG62106, HHSN268200782096C, HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C, N01HC95159, N01HC95160, N01HC95161, N01HC95162, N01HC95163, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169, RR024156, N02HL64278, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C, RC2HL102924, and CA137088); US National Institutes of Health grants (5RC2HL102419, HL080295, HL087652, HL103612, HL105756, HL120393, AG023629, DK063491, R01DK089256, R01HL087700, R01HL088215, R01HL117078, 1R01AG032098-01A1, U01-HG005152, R25CA094880, R01HL122684, R01HL04880, R01HL32262, R01DK49216, R01HL10001, R01DK092760, and R01OD017870); a Clinical and Translational Science Institute grant (UL1TR000124); a Danish Heart Foundation grant (07-10-R61-A1754-B838-22392F); a Biobanking and BioMolecular resources Research Infrastructure–The Netherlands (BBMRI-NL) grant (NWO 184.021.007); a Health Insurance Foundation grant (2012B233); and Academy of Finland grants (134309, 126925, 121584, 124282, 129378, 117787, and 41071).

This work was supported in part by the NIDDK Division of Intramural Research.

The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the US Department of Health and Human Services.

This work was carried out in part using computing resources at the University of Minnesota Supercomputing Institute.

Author information

Affiliations

  1. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.

    • Nathan Pankratz
  2. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ursula M Schick
    • , Yingchang Lu
    • , Erwin P Bottinger
    •  & Ruth J F Loos
  3. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Ursula M Schick
    •  & Alex P Reiner
  4. Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, Massachusetts, USA.

    • Yi Zhou
    • , Elliott J Hagedorn
    • , Bella Hu
    • , Vy M Nguyen
    • , Amanda M Rosa Di Sant
    •  & Leonard I Zon
  5. Department of Computational Medicine and Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Wei Zhou
  6. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Tarunveer Singh Ahluwalia
    • , Jette Bork-Jensen
    • , Niels Grarup
    • , Torben Hansen
    •  & Oluf Pedersen
  7. Steno Diabetes Center, Gentofte, Denmark.

    • Tarunveer Singh Ahluwalia
  8. Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA.

    • Maria Laura Allende
    •  & Richard L Proia
  9. School of Public Health, University of Wisconsin–Milwaukee, Milwaukee, Wisconsin, USA.

    • Paul L Auer
  10. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Jennifer A Brody
    • , James S Floyd
    •  & Bruce M Psaty
  11. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ming-Huei Chen
  12. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Ming-Huei Chen
    • , John D Eicher
    • , Andrew D Johnson
    • , Xiaoling Zhang
    • , L Adrienne Cupples
    •  & Christopher J O'Donnell
  13. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

    • Vinna Clavo
    • , Kristina Hunker
    • , Min-Lee Yang
    •  & Santhi K Ganesh
  14. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Vinna Clavo
    • , Kristina Hunker
    • , Min-Lee Yang
    •  & Santhi K Ganesh
  15. Population Sciences Branch, National Heart, Lung, and Blood Institute, Intramural Research Program, US National Institutes of Health, Bethesda, Maryland, USA.

    • John D Eicher
    •  & Andrew D Johnson
  16. Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.

    • Maarten Leusink
  17. Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Yingchang Lu
    •  & Ruth J F Loos
  18. Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland.

    • Leo-Pekka Lyytikäinen
    •  & Terho Lehtimäki
  19. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.

    • Ani Manichaikul
    •  & Stephen S Rich
  20. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.

    • Riccardo E Marioni
    • , Ian J Deary
    • , David C Liewald
    •  & John M Starr
  21. Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Riccardo E Marioni
  22. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.

    • Riccardo E Marioni
  23. Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.

    • Mike A Nalls
  24. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Raha Pazoki
    • , Frank J A van Rooij
    • , Oscar H Franco
    • , Albert Hofman
    • , Fernando Rivadeneira
    • , Andre G Uitterlinden
    •  & Abbas Dehghan
  25. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert Vernon Smith
    •  & Vilmundur Gudnason
  26. Faculty of Medicine, University of Iceland, Kopavogur, Iceland.

    • Albert Vernon Smith
    •  & Vilmundur Gudnason
  27. Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Xiaoling Zhang
  28. Department of Cardiology, Peking University First Hospital, Beijing, China.

    • Yan Zhang
    • , Jia Jia
    •  & Yong Huo
  29. Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Folkert W Asselbergs
  30. Durrer Center for Cardiogenetic Research, ICIN–Netherlands Heart Institute, Utrecht, the Netherlands.

    • Folkert W Asselbergs
  31. Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.

    • Folkert W Asselbergs
  32. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle
    •  & Megan L Grove
  33. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

    • Eric Boerwinkle
  34. Department of Medicine, Division of Hematology/Oncology, University of Vermont, Burlington, Vermont, USA.

    • Ingrid B Borecki
    • , Mary F Feitosa
    •  & Judy Wang
  35. Department of Medicine, Division of Hematology/Oncology, University of Vermont, Burlington, Vermont, USA.

    • Mary Cushman
  36. Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Paul I W de Bakker
  37. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Paul I W de Bakker
    •  & Mattijs E Numans
  38. Department of Psychology, University of Edinburgh, Edinburgh, UK.

    • Ian J Deary
  39. Jin Ding Street Community Health Center, Peking University Shougang Hospital, Beijing, China.

    • Liguang Dong
  40. Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Nora Franceschini
  41. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, US National Institutes of Health, Bethesda, Maryland, USA.

    • Melissa E Garcia
    • , Tamara B Harris
    •  & Lenore J Launer
  42. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Albert Hofman
  43. Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus, Ohio, USA.

    • Rebecca D Jackson
  44. Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.

    • Mika Kähönen
  45. Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark.

    • Allan Linneberg
    •  & Betina Heinsbæk Thuesen
  46. Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark.

    • Allan Linneberg
  47. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Allan Linneberg
  48. Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Yongmei Liu
  49. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ruth J F Loos
  50. Public Health and Primary Care, Leiden University Medical Centre, Leiden, the Netherlands.

    • Mattijs E Numans
  51. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

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

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

    • Bruce M Psaty
  54. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.

    • Olli T Raitakari
  55. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

    • Olli T Raitakari
  56. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Fernando Rivadeneira
    •  & Andre G Uitterlinden
  57. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Torrance, California, USA.

    • Jerome I Rotter
    •  & Kent D Taylor
  58. Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.

    • Jerome I Rotter
    •  & Kent D Taylor
  59. Geriatric Medicine Unit, University of Edinburgh, Edinburgh, UK.

    • John M Starr
  60. Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Colchester, Vermont, USA.

    • Russell P Tracy
  61. Department of Biochemistry, University of Vermont College of Medicine, Colchester, Vermont, USA.

    • Russell P Tracy
  62. Chronic Diseases Research Center, Peking University Shougang Hospital, Beijing, China.

    • Jiansong Wang
  63. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • L Adrienne Cupples
  64. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • James G Wilson
  65. Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, Intramural Research Program, US National Institutes of Health, Bethesda, Maryland, USA.

    • Christopher J O'Donnell
  66. Cardiology Section, Department of Medicine, Boston Veterans Administration Healthcare, Boston, Massachusetts, USA.

    • Christopher J O'Donnell
  67. Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.

    • Alex P Reiner

Consortia

  1. the CHARGE Consortium Hematology Working Group

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    N.P., Y. Zhou, Y. Zhang, E.P.B., I.J.D., O.H.F., M.E.G., V.G., T.H., T.B.H., A.H., L.J.L., A.L., O.P., J.M.S., A.D., Y.H., C.J.O'D., A.P.R., and S.K.G. designed the study. Y. Zhang, I.B.B., E.P.B., M.C., I.J.D., L.D., M.F.F., M.E.G., V.G., T.B.H., A.H., R.D.J., J.J., M.K., T.L., A.L., M.E.N., B.M.P., O.T.R., S.S.R., J.M.S., B.H.T., R.P.T., Jiansong Wang, and C.J.O'D. recruited and assessed participants. P.L.A., J.B.-J., N.G., L.-P.L., Y. Zhang, F.W.A., E.B., I.B.B., E.P.B., P.I.W.d.B., M.F.F., M.L.G., T.L., D.C.L., Y. Liu, S.S.R., F.R., J.I.R., K.D.T., and A.G.U. generated genotyping data. Y. Zhou, M.L.A., V.C., E.J.H., B.H., K.H., X.Z., V.M.N., A.M.R.D.S., R.L.P., and L.I.Z. performed functional experiments. N.P., U.M.S., T.S.A., M.L.A., P.L.A., J.B.-J., N.G., B.H., Y. Lu, M.A.N., R.P., A.V.S., Y. Zhang, J.S.F., N.F., M.L.G., R.J.F.L., B.M.P., A.D., L.A.C., J.G.W., R.L.P., L.I.Z., C.J.O'D., A.P.R., and S.K.G. analyzed and interpreted data. N.P., U.M.S., W.Z., T.S.A., J.B.-J., J.A.B., M.-H.C., J.D.E., N.G., A.D.J., M.L., Y. Lu, L.-P.L., A.M., R.E.M., M.A.N., R.P., A.V.S., F.J.A.v.R., M.-L.Y., Judy Wang, and A.P.R. performed statistical analysis. N.P., U.M.S., Y. Zhou, A.P.R., and S.K.G. wrote the manuscript. All authors were given the opportunity to comment and provide revisions to the manuscript text.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Nathan Pankratz or Santhi K Ganesh.

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    https://doi.org/10.1038/ng.3607

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