Multiple loci are associated with white blood cell phenotypes.

Area of Science:

• Genetics
• Hematology
• Immunology

Background:

• White blood cell (WBC) count is a common clinical measure with significant individual variability.
• The heritability of total WBC count and its subtypes is moderately established, but genetic influences are not fully understood.

Purpose of the Study:

• To identify and replicate genetic variants associated with total WBC count and five WBC subtypes within the normal hematological range.
• To explore functional relationships between genetic loci and WBC trait variability using gene expression and pathway analyses.

Main Methods:

• Genome-wide association study (GWAS) meta-analysis across multiple cohorts (discovery: 19,509 subjects; replication: 11,823 subjects).
• Analysis of seven genomic loci for total WBC count and five WBC subtypes.
• Gene expression and pathway-based analyses to investigate functional connectivity and biological consequences of identified loci.

Main Results:

• Ten significant associations with total WBC count and five WBC subtypes were identified and replicated across seven genomic loci.
• Seven novel associations were discovered, alongside three previously reported associations.
• Significant correlations were observed between genetic loci effect estimates and proximal gene expression in whole blood, indicating biological relevance.

Conclusions:

• This study significantly expands the understanding of genetic factors influencing normal variation in white blood cell counts and subtypes.
• The identified loci and functional analyses provide insights into the biological mechanisms underlying blood cell trait determination.
• Findings highlight the importance of large-scale collaborative efforts for robust genetic discovery across diverse populations.