Genetic prediction of blood cell reactivity and its potential causal influence on bone continuity and density disorders

BACKGROUND: This study aimed to investigate the potential causal relationship between genetically predicted human blood cell (HBC) reactivity and disorders of bone continuity, density, and structure. METHODS: We analyzed summary-level GWAS data for 91 HBC traits and two bone-related outcomes from publicly available sources, employing the inverse-variance weighted (IVW) method as the principal Mendelian randomization (MR) technique. The sensitivity analyses comprised MR-Egger regression and MR-PRESSO. RESULTS: MR analysis identified suggestive associations between red blood cell (RBC) perturbation response (Pam3CSK4), neutrophil perturbation response (side fluorescence coefficient of variation of neutrophil 4), Neutrophil perturbation response (colchicine), Monocyte perturbation response (TMAO perturbation) and bone continuity. The MR results are: [β: -0.13, odds ratio (OR): 0.88; 95% confidence interval (CI): 0.77, 0.99; p = 0.040], [β: 0.11, OR: 1.12, 95% CI: 1.02, 1.23; p = 0.016], [β: -0.11, OR: 0.90, 95% CI: 0.81, 0.99; p = 0.029] and [β: -0.04, OR: 0.96, 95% CI: 0.92, 0.99; p = 0.023]. In addition, Neutrophil perturbation response (forward scatter median of neutrophil 1), Unknown cell population perturbation response (nigericin) and other disorders of bone density and structure are also potential causal factors, with MR Result [β: 0.21, OR: 1.24, 95%CI: 1.01, 1.51; p = 0.034], [β: 0.03, OR: 1.03, 95% CI: 1.00, 1.06; p = 0.042]. Reverse Mendelian randomization sensitivity analysis showed a potential bidirectional association between specific HBC features and bone-related outcomes. CONCLUSIONS: This exploratory study offer valuable preliminary insights into the blood cell functional reactivity and bone health. The findings, while requiring independent validation, highlight plausible biological pathways for further elucidation.