Multiple Loci Are Associated with White Blood Cell Phenotypes

Abstract

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count—6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count—17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count—6p21, 19p13 at EPS15L1; monocyte count—2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

Common genetic factors for hematological traits in Humans

“…40 Associations at the PSMD3-CSF3 locus Since 2009, GWAS for total WBC and WBC subtypes have identified a number of genetic loci (Table 1). 26,28,[32][33][34][35][38][39][40][41][42] As expected, both common and unique associations for each WBC subtype were observed ( Figure 1a), which reflects their shared and non-shared processes in hematopoiesis. Because neutrophils comprise the majority of WBC, it is not surprising that the associations identified in GWAS for these two phenotypes were mostly shared.…”

“…39,41,42 ITGA4 encodes the a4 chain of integrin, which mediates the migration of WBC into the tissues. 54 The variants of the ITGA4 locus were shown to regulate the expression of ITGA4 messenger RNA in monocytes.…”

“…10,41 Compared with the other WBC subtypes, GWAS for lymphocytes have been less successful. 32,[38][39][40][41] This may be because the lymphocytes can be further subdivided, and these sub-phenotypes have not been sufficiently examined enough. A GWAS focusing on lymphocyte subsets by Ferreia et al 33 successfully identified associated genetic loci, and additional accumulations of the studies on lymphocytes subsets would be desirable.…”

“…Recently, three large-scale GWAS for WBC and WBC subtypes were concurrently reported for European (by the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium), 39,57 African American (by the COGENT (Continental Origins Figure 1 Shared associations between white blood cells' (WBC) subtypes. Shared associations of genetic loci with WBC subtypes in a Japanese population.…”

The role of eosinophils and basophils in allergic diseases considering genetic findings

“…Three genome-wide association studies (GWAS) of eosinophil and/or basophil cell counts have been conducted in European and Asian populations [33][34][35]. These GWAS led to detection of four loci with pleiotropic effect on eosinophil and basophil counts in both European and Asian samples: GATA2 (GATA binding protein 2, 3q21), MHC region (major histocompatibility complex, 6p21), HBS1L-MYB (HBS1-like -myeloblastosis viral oncogene homolog, 6q23), and ERG (erythroblastosis virus E26 oncogene homolog, 21q22) [33,35].…”