Pathway-Level Reorganization of Genetic Signals Associated with Low Bone Mineral Density Across the Menopausal Transition.

Osteoporosis in women is strongly influenced by menopause, a major physiological transition that reshapes bone metabolism. Although low bone mineral density (BMD) in premenopausal women and osteoporosis in postmenopausal women share the clinical outcome of skeletal fragility, it remains unclear whether they reflect a shared molecular program or distinct regulatory mechanisms. Here, we compared genetic signals associated with premenopausal and postmenopausal low BMD in Korean women using two independent genotyping platforms with distinct variant coverage. After allele harmonization and heterogeneity testing, variants were classified as reversal signals, showing directionally discordant effects across menopausal status, or stable signals, showing concordant effects. Gene-level association analysis was performed using Multi-marker Analysis of GenoMic Annotation (MAGMA), followed by functional enrichment and network-based analyses. Reversal and stable signals showed distinct biological patterns. Reversal signals consistently converged on cyclic nucleotide-related pathways, including cyclic adenosine monophosphate/cyclic guanosine monophosphate (cAMP/cGMP) signaling and nitric oxide-mediated processes, whereas stable signals were more broadly distributed across pathways related to ion homeostasis, cell-substrate adhesion, and structural maintenance. These pathway-level patterns were reproducible across platforms despite limited SNP-level overlap. These findings suggest that low BMD across the menopausal transition is better resolved at the gene and pathway levels than at the level of individual SNPs.