Bridging muscle and bone: shared genetic signatures of osteosarcopenia revealed by reverse Gene Ontology lookup

Osteosarcopenia, the coexistence of osteoporosis and sarcopenia, is an emerging geriatric syndrome that markedly increases frailty, fracture risk, and disability. Although traditionally considered distinct conditions, growing evidence indicates that both share convergent molecular pathways linking bone and muscle degeneration. To elucidate their shared genetic background, we applied GOReverseLookup, a Gene Ontology–based reverse lookup tool, using 367 curated GO terms representing key disease mechanisms. The analysis, integrating ortholog data from four vertebrate species, identified 37 genes significantly enriched for annotations related to both disorders (FDR < 5 × 10⁻⁸). Among these, 14 genes had no prior association with either condition, and five (RBCK1, TERF2IP, LGALS9, ZBTB7A, RPS3) showed moderate expression in both bone and muscle. KEGG enrichment revealed 15 pathways, prominently NF-κB, TNF, osteoclast differentiation, necroptosis, and cytosolic DNA-sensing signaling, highlighting an inflammatory and immune-regulatory convergence. These findings identify novel, biologically plausible candidates and pathways underlying osteosarcopenia, and validate GOReverseLookup as a transparent approach for cross-phenotype gene discovery. The integration of GO-based inference with expression and pathway analysis provides a reproducible framework for exploring multi-tissue syndromes.