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