MR-supported candidate genes and pathway analysis between ischemic stroke and osteoporosis: an integrated multi-omics study

The global prevalence of ischemic stroke (IS) and osteoporosis (OP) is rising, posing significant public health challenges in aging populations. We aimed to uncover shared genetic factors and elucidate the molecular mechanisms linking IS and OP to identify potential targets for integrated preventive and therapeutic interventions.

A comprehensive multi-omics analysis was performed to assess associations and molecular pathways connecting IS and OP. Summary statistics for IS and OP were integrated with expression quantitative trait loci data from the eQTLGen consortium (n = 4,463) to identify common significant single nucleotide polymorphisms (SNPs) related to both diseases. Follow-up transcriptomic profiling and single-cell RNA sequencing were employed to investigate functional pathways, regulatory networks, and cell-type-specific expression patterns associated with these loci. Finally, the expression levels of shared molecules were confirmed using animal models, and subsequent functional analyses were conducted on these genes.

Two-sample Mendelian randomization identified FCGR2B and CYBB as exploratory MR-supported candidate genes with shared eQTL instruments. Transcriptome-wide analysis linked these loci to immune-metabolic pathways, including oxidative stress response (FDR = 0.003) and interferon-γ signaling (FDR = 0.01). Mouse-derived ischemic-stroke single-cell RNA-seq provided exploratory cell-type localization: Fcgr2b and Cybb were preferentially enriched in monocytes and macrophages (FDR < 0.05), whereas Sirt1 was predominantly localized to endothelial cells and tissue stem cells in the diseased mouse microenvironment. Of note, the osteoporosis single-cell dataset (GSE147287) contained only one OP patient, and its cell-type patterns should therefore be interpreted as exploratory case observations rather than generalized findings. Regulatory network analysis identified the cisbp:M1399 transcription factor motif (NES = 4.12) with the highest enrichment score, which is predicted to separately regulate the transcription of FCGR2B, CYBB and SIRT1. Pathway enrichment analysis revealed metabolic reprogramming (AUC = 0.78, p=0.004) as a key mechanistic node differentiating high-and low-expression cell groups. The expression levels of the shared molecules were validated in a mouse model.

This multi-omics study implicates immune-metabolic dysregulation as a shared pathological feature of ischemic stroke and osteoporosis. FCGR2B, CYBB and SIRT1 are exploratory MR-supported candidate genes putatively associated with both diseases, offering potential clues for dual-purpose preventive and therapeutic strategies for age-related IS-OP comorbidity.