Immune cell-specific gene expression and its causal role in osteoporosis and bone mineral density: Insights from single-cell eQTL and GWAS data integration

Osteoporosis (OP) is a common metabolic bone disease, with genetic and immune system factors playing crucial roles in its pathogenesis. With the advancement of single-cell RNA sequencing (scRNA-seq), gene expression regulation at the immune cell subtype level has been more deeply explored. In this study, we integrated single-cell expression quantitative trait loci data with genome-wide association study data to systematically investigate the causal relationships between immune cell-specific gene expression and OP risk/ bone mineral density (BMD). Through summary-data-based Mendelian randomization, two-sample Mendelian randomization, Steiger directionality tests, and colocalization analysis, we identified 7 genes in specific immune cell types that are associated with OP/BMD phenotypes, including GLTPD1, NPRL3, NCR3, HBQ1, POU5F1, CDC42, and C10orf32. Specifically, GLTPD1, NPRL3, NCR3, HBQ1, and POU5F1 showed significant causal effects on OP risk, CDC42 was associated with total-body BMD in the 0 to 15 age group, and C10orf32 showed significant causal effects with total-body BMD in the >60 age group. Our findings provide new insights into the role of the immune system in bone metabolism and offer important theoretical support for further research on immune-mediated treatment strategies for OP.