Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 × 10−13). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 × 10−22) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 × 10−7) and WBC count (P = 3.1 × 10−5). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits.

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We thank all participants and staff of the MHI Biobank and acknowledge the technical support of the Beaulieu-Saucier MHI Pharmacogenomic Center. This work was supported by the Centre of Excellence in Personalized Medicine (CEPMed), Fonds de Recherche du Québec–Santé (FRQS), the Canada Research Chair program and the MHI Foundation. The WHI program is funded by the National Heart, Lung, and Blood Institute, the US National Institutes of Health and the US Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C). Exome chip data and analysis were supported through the Exome Sequencing Project (NHLBI RC2 HL-102924, RC2 HL-102925 and RC2 HL-102926), the Genetics and Epidemiology of Colorectal Cancer Consortium (NCI CA137088), the Genomics and Randomized Trials Network (NHGRI U01-HG005152) and a National Cancer Institute training grant (R25CA094880). The authors thank the WHI investigators and staff for their dedication and the study participants for making the program possible. SHIP is part of the Community Medicine Research network of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg–West Pomerania, and the network Greifswald Approach to Individualized Medicine (GANI_MED) funded by the Federal Ministry of Education and Research (grant 03IS2061A). Generation of ExomeChip data has been supported by the Federal Ministry of Education and Research (grant 03Z1CN22) and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of Siemens AG and the Caché Campus program of InterSystems. G.A.D. acknowledges support from US National Institutes of Health award P01AI061093.

Author information

Author notes

    • George A Diaz
    • , Alexander P Reiner
    •  & Guillaume Lettre

    These authors jointly directed this work.


  1. School of Public Health, University of Wisconsin–Milwaukee, Milwaukee, Wisconsin, USA.

    • Paul L Auer
  2. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Paul L Auer
    • , Ursula Schick
    • , Chris Carlson
    • , Jeff Haessler
    • , Charles Kooperberg
    • , Ulrike Peters
    • , Li Hsu
    •  & Alexander P Reiner
  3. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.

    • Alexander Teumer
    • , Frank Schmidt
    •  & Uwe Völker
  4. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Andrew O'Shaughnessy
    •  & George A Diaz
  5. Montreal Heart Institute, Montreal, Quebec, Canada.

    • Ken Sin Lo
    • , Nathalie Chami
    • , Simon de Denus
    • , Marie-Pierre Dubé
    • , Louis-Philippe Lemieux Perreault
    • , John D Rioux
    • , Valérie Turcot
    • , Jean-Claude Tardif
    •  & Guillaume Lettre
  6. Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada.

    • Simon de Denus
    • , Marie-Pierre Dubé
    • , John D Rioux
    • , Jean-Claude Tardif
    •  & Guillaume Lettre
  7. Faculty of Pharmacy, Université de Montréal, Montreal, Québec, Canada.

    • Simon de Denus
    • , Marie-Pierre Dubé
    • , John D Rioux
    • , Jean-Claude Tardif
    •  & Guillaume Lettre
  8. Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, Ohio, USA.

    • Rebecca D Jackson
  9. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Matthias Nauck
  10. Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.

    • Ulrike Peters
    •  & Alexander P Reiner
  11. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Henry Völzke
  12. Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Andreas Greinacher
  13. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • George A Diaz


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P.L.A., G.A.D., A.P.R. and G.L. conceived and designed the experiments. P.L.A., A.T., U.S., A.O., K.S.L., G.A.D., A.P.R. and G.L. performed the experiments. P.L.A., A.T., U.S., A.O., K.S.L., G.A.D., A.P.R. and G.L. analyzed the data. All authors contributed reagents and materials. P.L.A., G.A.D., A.P.R. and G.L. wrote the manuscript with contributions from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to George A Diaz or Alexander P Reiner or Guillaume Lettre.

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