Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits

Nat Genet. 2014 Jun;46(6):629-34. doi: 10.1038/ng.2962. Epub 2014 Apr 28.


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.

Publication types

  • Meta-Analysis

MeSH terms

  • Adult
  • Aged
  • Chemotaxis
  • Congenital Bone Marrow Failure Syndromes
  • Exome
  • Female
  • Frameshift Mutation
  • Genome-Wide Association Study
  • Genotype
  • Hematocrit
  • Hematopoiesis
  • Hemoglobins / genetics*
  • Humans
  • Janus Kinase 2 / genetics
  • Leukocyte Count*
  • Male
  • Middle Aged
  • Mutation, Missense
  • Neutropenia / congenital*
  • Neutropenia / genetics
  • Pedigree
  • Platelet Count*
  • Receptors, Interleukin-8B / genetics*


  • Hemoglobins
  • Receptors, Interleukin-8B
  • JAK2 protein, human
  • Janus Kinase 2

Supplementary concepts

  • Neutropenia, Severe Congenital, Autosomal Recessive 3