Rare coding variants pinpoint genes that control human hematological traits

PLoS Genet. 2017 Aug 7;13(8):e1006925. doi: 10.1371/journal.pgen.1006925. eCollection 2017 Aug.


The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45-0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39-0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.

MeSH terms

  • Asthma / blood*
  • Asthma / genetics
  • Databases, Genetic
  • Endometriosis / blood*
  • Endometriosis / genetics
  • Female
  • Fibrin Fibrinogen Degradation Products / genetics
  • Fibrin Fibrinogen Degradation Products / metabolism
  • Gene Frequency
  • Genetic Loci
  • Genome, Human*
  • Genome-Wide Association Study
  • Humans
  • Interleukin-33 / genetics
  • Interleukin-33 / metabolism
  • Linear Models
  • Logistic Models
  • Male
  • Mutation, Missense
  • Phenotype
  • Plasminogen / genetics
  • Plasminogen / metabolism
  • Platelet Count
  • Polymorphism, Single Nucleotide*
  • Principal Component Analysis
  • Protein Splicing / genetics
  • Rhinitis, Allergic / blood*
  • Rhinitis, Allergic / genetics
  • Sequence Analysis, DNA


  • Fibrin Fibrinogen Degradation Products
  • Interleukin-33
  • fibrin fragment D
  • Plasminogen