Causal genes for osteoporosis: Mendelian randomization analysis with multilayer xQTL data

Osteoporosis is a highly heritable metabolic bone disorder characterized by low bone mass and increased fracture risk. However, the causal genes underlying disease susceptibility remain incompletely understood. In this study, we employed a summary-data-based Mendelian randomization (SMR) framework to identify genes with potential causal effects on osteoporosis by integrating genome-wide association study summary statistics from the FinnGen consortium with multilayer molecular quantitative trait loci (xQTL) data, including expression, splicing, methylation, and protein QTLs across multiple tissues (106 xQTL datasets in total). The heterogeneity in dependent instruments (HEIDI) test was applied to distinguish pleiotropic associations from linkage disequilibrium-driven effects. Functional characterization was further conducted using Gene Ontology and KEGG pathway enrichment analyses, protein-protein interaction network construction, drug-gene enrichment analysis, and molecular docking. Using this integrative approach, we identified 15 high-confidence genes - CEP112, CKB, GID4, MEOX1, MEPE, PPP6R3, RGS9, RSPO3, SERPINA1, SFRP4, SOST, SPP1, SREBF1, TOM1L2, and ZBTB48 - showing evidence of causal associations with osteoporosis after stringent multiple-testing correction and HEIDI filtering. These genes included established regulators of bone metabolism as well as novel candidates involved in metabolic regulation and signal transduction. Enrichment analyses highlighted pathways related to Wnt and bone morphogenetic protein signaling, extracellular matrix organization, and metabolic processes, while network analysis revealed substantial functional connectivity among the prioritized genes. In addition, drug-gene enrichment analysis prioritized β-carotene, apocarotenal, and bezafibrate as potential therapeutic candidates, with molecular docking supporting stable interactions with key protein targets. Overall, this study provides robust genetic evidence for causal molecular regulators of osteoporosis and highlights potential therapeutic targets, offering a clinically relevant resource for future functional validation and translational research.