Genome-wide association study and predictors of neonatal blood cell traits in Hispanic newborns

The role of heritable genetic variation in hematologic traits in adults is well established, yet the genetic architecture of neonatal blood cell traits is unknown. Leveraging flow cytometry profiling in cord blood samples from 382 Hispanic newborns, we conducted genome-wide association studies (GWASs) of 24 blood cell phenotypes to assess the impact of genetic and birth-related characteristics. We identified six genome-wide significant loci, including a signal at chromosome 2p11.2 spanning CD8A and CD8B that was associated with CD4⁺CD8⁺ double-positive T cells (rs35505884-C: p = 6.83 × 10^-26). The lead variant showed strongly differentiated allele frequencies between European (22.1%) and admixed American (11.8%) populations and was associated with global (p = 2.51 × 10^-6) and local (p = 2.01 × 10^-8) Indigenous American ancestry. Colocalization with single-cell expression quantitative trait loci (eQTLs) revealed convergence of GWAS effects with regulation of CD8A expression in natural killer cells and CD4⁺ effector memory T cells with posterior probability (PP_H4) >0.85. A locus at 6p21.33 was associated with CD4^-CD8⁺ cytotoxic T cells (rs2853973-C, p = 3.90 × 10^-8) and colocalized with MICA-AS1 expression across multiple immune cell types (PP_H4 > 0.85). Additional nominal genome-wide significant loci were detected for total CD45⁺ lymphocytes, CD19⁺CD56⁺CD16⁺ natural killer cells, and CD4⁺CD8^- helper T cells. C-section delivery and biological sex significantly altered blood cell profiles, with the largest magnitudes of association observed between C-section and total CD3⁺ T cells (β = 0.39) and CD4⁺ helper T cells (β = 0.39), and between female sex and CD4⁺CD8^- (β = 0.39) and CD4^-CD8⁺ T cells (β = -0.36). Our study demonstrates that blood cell composition at birth is under strong genetic regulation in Hispanic newborns, highlighting the value of studying complex traits in early life.