Single‐Cell Integration of <scp>BMD GWAS</scp> Results Prioritize Candidate Genes Influencing Age‐Related Bone Loss

The regulation of bone mineral density (BMD) is highly influenced by genetics and age. Although genome-wide association studies (GWAS) for BMD have uncovered many genes through their proximity to associated variants (variant nearest-neighbor [VNN] genes), the cell-specific mechanisms each VNN gene remain unclear. This primarily due inability prioritize these cell type age-related expression. Using transcriptomics, we found that expression was upregulated in marrow from aged mice. Candidate GWAS were investigated using single-cell RNA-sequencing (scRNA-seq) datasets enrich signatures. candidate are enriched osteo-lineage cells, osteocytes, hypertrophic chondrocytes, Lepr+ mesenchymal stem cells. These data used generate a “blueprint” Cre-loxp mouse line selection functional validation further investigation role maintenance throughout aging. In VNN-gene-enriched Sparc, encoding extracellular matrix (ECM) protein osteonectin, robustly expressed. This, along with numerous other ECM genes, indicates likely roles deposition osteoblasts. Overall, provide supporting streamlined translation potential novel therapeutic targets treatment osteoporosis. © 2023 Authors. JBMR Plus published Wiley Periodicals LLC on behalf American Society Bone Mineral Research.