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.
Highlights
The White blood cell (WBC) count, a classic marker of immune or inflammatory response, varies substantially among healthy individuals
The counts of constituent cell subtypes comprising the WBC count measure are assayed as part of a standard clinical WBC differential test
Cohort specific data was supplied by the CHARGE, HeamGen, and Italian Network on Genetic Isolates (INGI) consortia, as well as independent collaborative studies
Summary
The WBC count, a classic marker of immune or inflammatory response, varies substantially among healthy individuals. The total WBC count is directly associated with many cardiovascular disease risk factors, such as higher blood pressure, cigarette smoking, adiposity, lower socioeconomic status, and higher levels of plasma inflammatory markers [13]. The substantially lower neutrophil count and total WBC count in African Americans compared to European-ancestry individuals seems to be at least partially explained by a regulatory variant in the Duffy Antigen Receptor for Chemokine (DARC) gene, which accounts for ,20% of total variation in the measures [15,16]. Recent studies have sought to investigate the common genetic variants associated with several blood count traits in European-ancestry and Japanese individuals, but have not focused on the multiple cell types comprising the total WBC count measurement [17,18,19,20]
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