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Objective <p>To systematically explore causal relationships between chondrosarcoma and angiogenesis-related gene expression using Mendelian randomization (MR) and transcriptome-wide association study (TWAS) approaches, and identify potential therapeutic targets.</p> Methods <p>Based on whole blood tissue gene expression data, summary-data-based Mendelian randomization (SMR) analysis was performed to examine causal associations between 25 angiogenesis-related candidate genes and chondrosarcoma risk. Simultaneously, transcriptome-wide association study (TWAS) was conducted covering 22 autosomes, calculating Z-scores and P-values to assess the strength of association between gene expression and disease. Key findings were validated by RT-qPCR in chondrosarcoma cell lines versus normal chondrocytes.</p> Results <p>SMR analysis identified significant causal associations after correction. LINC00984 showed the strongest risk association (OR = 5.243, <i>P</i> = 1.10 × 10<sup>-2</sup>), while TXNDC2 also demonstrated risk effects (OR = 3.555, <i>P</i> = 5.09 × 10<sup>-3</sup>). Protective genes included MPL28 (OR = 0.070, <i>P</i> = 1.40 × 10<sup>-2</sup>) and RP11-474N24.6 (OR = 0.287, <i>P</i> = 1.92 × 10<sup>-3</sup>). TWAS identified significant signals on chromosomes 18–19 and 22. Functional analysis confirmed enrichment in VEGF and HIF-1 pathways. RT-qPCR validation showed risk genes were upregulated 3.2–8.2-fold in tumor cells, while protective genes were downregulated 58–78% (all <i>P</i> &lt; 0.01).</p> Conclusion <p>This study identified multiple angiogenesis-regulatory genes significantly associated with chondrosarcoma through large-scale genetic analysis, revealing complex molecular mechanisms of disease development and providing important genetic evidence for precision therapeutic strategy development.</p>

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Mendelian randomization analysis of causal relationships between chondrosarcoma and angiogenesis related genes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • Peng Xie,
  • Xiangtao Bian,
  • Wei Wei,
  • Hai Teng,
  • Chengbo Wang

摘要

Objective

To systematically explore causal relationships between chondrosarcoma and angiogenesis-related gene expression using Mendelian randomization (MR) and transcriptome-wide association study (TWAS) approaches, and identify potential therapeutic targets.

Methods

Based on whole blood tissue gene expression data, summary-data-based Mendelian randomization (SMR) analysis was performed to examine causal associations between 25 angiogenesis-related candidate genes and chondrosarcoma risk. Simultaneously, transcriptome-wide association study (TWAS) was conducted covering 22 autosomes, calculating Z-scores and P-values to assess the strength of association between gene expression and disease. Key findings were validated by RT-qPCR in chondrosarcoma cell lines versus normal chondrocytes.

Results

SMR analysis identified significant causal associations after correction. LINC00984 showed the strongest risk association (OR = 5.243, P = 1.10 × 10-2), while TXNDC2 also demonstrated risk effects (OR = 3.555, P = 5.09 × 10-3). Protective genes included MPL28 (OR = 0.070, P = 1.40 × 10-2) and RP11-474N24.6 (OR = 0.287, P = 1.92 × 10-3). TWAS identified significant signals on chromosomes 18–19 and 22. Functional analysis confirmed enrichment in VEGF and HIF-1 pathways. RT-qPCR validation showed risk genes were upregulated 3.2–8.2-fold in tumor cells, while protective genes were downregulated 58–78% (all P < 0.01).

Conclusion

This study identified multiple angiogenesis-regulatory genes significantly associated with chondrosarcoma through large-scale genetic analysis, revealing complex molecular mechanisms of disease development and providing important genetic evidence for precision therapeutic strategy development.