Unfolding of hidden white blood cell count phenotypes for gene discovery using latent class mixed modeling

Genes Immun. 2019 Sep;20(7):555-565. doi: 10.1038/s41435-018-0051-y. Epub 2018 Nov 21.


Resting-state white blood cell (WBC) count is a marker of inflammation and immune system health. There is evidence that WBC count is not fixed over time and there is heterogeneity in WBC trajectory that is associated with morbidity and mortality. Latent class mixed modeling (LCMM) is a method that can identify unobserved heterogeneity in longitudinal data and attempts to classify individuals into groups based on a linear model of repeated measurements. We applied LCMM to repeated WBC count measures derived from electronic medical records of participants of the National Human Genetics Research Institute (NHRGI) electronic MEdical Record and GEnomics (eMERGE) network study, revealing two WBC count trajectory phenotypes. Advancing these phenotypes to GWAS, we found genetic associations between trajectory class membership and regions on chromosome 1p34.3 and chromosome 11q13.4. The chromosome 1 region contains CSF3R, which encodes the granulocyte colony-stimulating factor receptor. This protein is a major factor in neutrophil stimulation and proliferation. The association on chromosome 11 contain genes RNF169 and XRRA1; both involved in the regulation of double-strand break DNA repair.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Databases, Genetic
  • Electronic Health Records
  • Female
  • Genome-Wide Association Study
  • Humans
  • Latent Class Analysis
  • Leukocyte Count / methods*
  • Leukocytes / classification*
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Proteins / genetics
  • Receptors, Colony-Stimulating Factor / genetics
  • Ubiquitin-Protein Ligases / genetics


  • CSF3R protein, human
  • Proteins
  • Receptors, Colony-Stimulating Factor
  • XRRA1 protein, human
  • RNF169 protein, human
  • Ubiquitin-Protein Ligases