2SNP heritability and effects of genetic variants for neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio

J Hum Genet. 2017 Nov;62(11):979-988. doi: 10.1038/jhg.2017.76. Epub 2017 Aug 3.


Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are important biomarkers for disease development and progression. To gain insight into the genetic causes of variance in NLR and PLR in the general population, we conducted genome-wide association (GWA) analyses and estimated SNP heritability in a sample of 5901 related healthy Dutch individuals. GWA analyses identified a new genome-wide significant locus on the HBS1L-MYB intergenic region for PLR, which replicated in a sample of 2538 British twins. For platelet count, we replicated three known genome-wide significant loci in our cohort (at CCDC71L-PIK3CG, BAK1 and ARHGEF3). For neutrophil count, we replicated the PSMD3 locus. For the identified top SNPs, we found significant cis and trans expression quantitative trait loci effects for several loci involved in hematological and immunological pathways. Linkage Disequilibrium score (LD) regression analyses for PLR and NLR confirmed that both traits are heritable, with a polygenetic SNP heritability for PLR of 14.1%, and for NLR of 2.4%. Genetic correlations were present between ratios and the constituent counts, with the genetic correlation (r=0.45) of PLR with platelet count reaching statistical significance. In conclusion, we established that two important biomarkers have a significant heritable SNP component, and identified the first genome-wide locus for PLR.

MeSH terms

  • Biomarkers / blood*
  • Blood Platelets*
  • Class Ib Phosphatidylinositol 3-Kinase / genetics
  • Cohort Studies
  • Female
  • GTP-Binding Proteins / genetics*
  • Genome-Wide Association Study*
  • HSP70 Heat-Shock Proteins / genetics*
  • Humans
  • Linkage Disequilibrium / genetics
  • Lymphocytes / metabolism
  • Male
  • Neutrophils / metabolism
  • Peptide Elongation Factors / genetics*
  • Platelet Count
  • Polymorphism, Single Nucleotide / genetics
  • Proteasome Endopeptidase Complex / genetics
  • Quantitative Trait Loci / genetics*
  • Rho Guanine Nucleotide Exchange Factors / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / genetics


  • ARHGEF3 protein, human
  • BAK1 protein, human
  • Biomarkers
  • HSP70 Heat-Shock Proteins
  • Peptide Elongation Factors
  • Rho Guanine Nucleotide Exchange Factors
  • bcl-2 Homologous Antagonist-Killer Protein
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human
  • Proteasome Endopeptidase Complex
  • proteasome activator PA700 subunit p58, human
  • GTP-Binding Proteins
  • HBS1L protein, human