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

Nature Genetics volume 48, pages 867–876 (2016)Cite this article

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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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Figure 1: Forest plots of the S1PR4 variant encoding p.Arg365Leu for total WBC count.
Figure 2
Figure 3: Blood neutrophils in S1pr4−/− mice.
Figure 4: Reduction in neutrophil counts in zebrafish embryos with decreased s1pr4 expression by morpholino-mediated knockdown with two independent morpholino oligonucleotides.
Figure 5: Neutrophil migration in response to injury is altered in zebrafish embryos with low s1pr4 gene expression.

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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

Authors and 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. Department of Medicine, Cardiovascular Health Research Unit, 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. Division of Public Health Sciences, Center for Human Genetics, 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. Department of Medicine, Cardiology Section, 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

the CHARGE Consortium Hematology Working Group

  • Nathan Pankratz
  • , Ursula M Schick
  • , Yi Zhou
  • , Wei Zhou
  • , Tarunveer Singh Ahluwalia
  • , Maria Laura Allende
  • , Paul L Auer
  • , Jette Bork-Jensen
  • , Jennifer A Brody
  • , Ming-Huei Chen
  • , Vinna Clavo
  • , John D Eicher
  • , Niels Grarup
  • , Elliott J Hagedorn
  • , Bella Hu
  • , Kristina Hunker
  • , Andrew D Johnson
  • , Maarten Leusink
  • , Yingchang Lu
  • , Leo-Pekka Lyytikäinen
  • , Ani Manichaikul
  • , Riccardo E Marioni
  • , Mike A Nalls
  • , Raha Pazoki
  • , Albert Vernon Smith
  • , Frank J A van Rooij
  • , Min-Lee Yang
  • , Xiaoling Zhang
  • , Yan Zhang
  • , Folkert W Asselbergs
  • , Eric Boerwinkle
  • , Ingrid B Borecki
  • , Erwin P Bottinger
  • , Mary Cushman
  • , Paul I W de Bakker
  • , Ian J Deary
  • , Liguang Dong
  • , Mary F Feitosa
  • , James S Floyd
  • , Nora Franceschini
  • , Oscar H Franco
  • , Melissa E Garcia
  • , Megan L Grove
  • , Vilmundur Gudnason
  • , Torben Hansen
  • , Tamara B Harris
  • , Albert Hofman
  • , Rebecca D Jackson
  • , Jia Jia
  • , Mika Kähönen
  • , Lenore J Launer
  • , Terho Lehtimäki
  • , David C Liewald
  • , Allan Linneberg
  • , Yongmei Liu
  • , Ruth J F Loos
  • , Vy M Nguyen
  • , Mattijs E Numans
  • , Oluf Pedersen
  • , Bruce M Psaty
  • , Olli T Raitakari
  • , Stephen S Rich
  • , Fernando Rivadeneira
  • , Amanda M Rosa Di Sant
  • , Jerome I Rotter
  • , John M Starr
  • , Kent D Taylor
  • , Betina Heinsbæk Thuesen
  • , Russell P Tracy
  • , Andre G Uitterlinden
  • , Jiansong Wang
  • , Judy Wang
  • , Abbas Dehghan
  • , Yong Huo
  • , L Adrienne Cupples
  • , James G Wilson
  • , Richard L Proia
  • , Leonard I Zon
  • , Christopher J O'Donnell
  • , Alex P Reiner
  •  & Santhi K Ganesh

Contributions

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.

Corresponding authors

Correspondence to Nathan Pankratz or Santhi K Ganesh.

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Competing interests

The author declare no competing financial interests.

Supplementary information

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Supplementary Figures 1–8 and Supplementary Note. (PDF 2138 kb)

Supplementary Tables 1–16

Supplementary Tables 1–16. (XLSX 619 kb)

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the CHARGE Consortium Hematology Working Group. Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits. Nat Genet 48, 867–876 (2016). https://doi.org/10.1038/ng.3607

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