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Background <p>Emerging evidence links macrophage polarization to osteoporosis pathogenesis, yet the specific causal genes and underlying molecular mechanisms remain poorly defined.</p> Methods <p>We used a multi-stage, summary-data-based Mendelian randomization (SMR) framework to integrate blood-derived methylation, expression, and protein quantitative trait loci (mQTL, eQTL, and pQTL) with large-scale osteoporosis genome-wide association study (GWAS) datasets. We performed SMR and colocalization analyses across predefined macrophage polarization-related genes, followed by multi-omics integration. To explore external expression patterns, we examined mRNA levels of selected genes in an independent femoral bone tissue microarray dataset (GSE230665; 12 postmenopausal osteoporosis cases and 3 controls), and conducted pathway enrichment and network analyses of prioritized genes.</p> Results <p>Our multi-omics analysis identified 66 genes at the methylation level, 14 at the expression level, and 5 proteins with SMR evidence for association with osteoporosis. Integrative analyses highlighted <i>DNMT3A</i>, <i>CTSK</i>, and <i>CDCA4</i> at the methylation–expression interface, and AGER, <i>F2</i>, and HMOX1 at the protein level, as candidates with genetically predicted associations with osteoporosis risk. In the external femoral bone tissue dataset, AGER mRNA expression was lower in osteoporosis patients than in controls (<i>p</i> = 0.0044), whereas <i>DNMT3A</i> mRNA expression was higher in patients (<i>p</i> = 0.018), opposite to the protective association suggested by eQTL-based SMR, suggesting complex tissue-specific or compensatory regulation.</p> Conclusions <p>This blood QTL-based multi-omics SMR study prioritizes macrophage polarization-related genes and proteins with genetically predicted associations with osteoporosis risk and suggests links between peripheral immune signaling and bone metabolism. These findings are exploratory and hypothesis-generating and require validation in bone marrow-specific and functional studies.</p> Clinical trial number <p>Not applicable.</p>

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Macrophage polarization-related genes with potential causal roles in osteoporosis: a multi-omics Mendelian randomization study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月18日

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  • Feng Xiong,
  • Aoqi Zang,
  • Ming Zhu,
  • Bingxu Ma,
  • Jun Zhang,
  • Peitai Liu,
  • Feng Qian,
  • Jianzhong Guan,
  • Hui Xu

摘要

Background

Emerging evidence links macrophage polarization to osteoporosis pathogenesis, yet the specific causal genes and underlying molecular mechanisms remain poorly defined.

Methods

We used a multi-stage, summary-data-based Mendelian randomization (SMR) framework to integrate blood-derived methylation, expression, and protein quantitative trait loci (mQTL, eQTL, and pQTL) with large-scale osteoporosis genome-wide association study (GWAS) datasets. We performed SMR and colocalization analyses across predefined macrophage polarization-related genes, followed by multi-omics integration. To explore external expression patterns, we examined mRNA levels of selected genes in an independent femoral bone tissue microarray dataset (GSE230665; 12 postmenopausal osteoporosis cases and 3 controls), and conducted pathway enrichment and network analyses of prioritized genes.

Results

Our multi-omics analysis identified 66 genes at the methylation level, 14 at the expression level, and 5 proteins with SMR evidence for association with osteoporosis. Integrative analyses highlighted DNMT3A, CTSK, and CDCA4 at the methylation–expression interface, and AGER, F2, and HMOX1 at the protein level, as candidates with genetically predicted associations with osteoporosis risk. In the external femoral bone tissue dataset, AGER mRNA expression was lower in osteoporosis patients than in controls (p = 0.0044), whereas DNMT3A mRNA expression was higher in patients (p = 0.018), opposite to the protective association suggested by eQTL-based SMR, suggesting complex tissue-specific or compensatory regulation.

Conclusions

This blood QTL-based multi-omics SMR study prioritizes macrophage polarization-related genes and proteins with genetically predicted associations with osteoporosis risk and suggests links between peripheral immune signaling and bone metabolism. These findings are exploratory and hypothesis-generating and require validation in bone marrow-specific and functional studies.

Clinical trial number

Not applicable.