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<p>Genome-wide association studies (GWAS) identify genetic associations for glaucoma, particularly its subtype, open-angle glaucoma (OAG). Translating these disease-genetic associations into therapeutic targets and potential drugs, however, remains a challenge. We propose to address this post-GWAS challenge with the priority index solution to glaucoma (PIG), which leverages genetic and network evidence for drug target prioritisation. PIG not only recovers clinical proof-of-concept targets for OAG but also supports integrated analysis for pathway crosstalk identification. The latter further enables crosstalk-based therapeutic discovery: removal analysis to identify key nodes with the crosstalk; drug repurposing analysis to identify candidate drugs; and construction of a&#xa0;prioritisation map across diseases to reveal disease-specific targeting potential for OAG. These multifaceted functionalities provide therapeutic insights into targeting the FoxO signaling&#xa0;pathway, which includes tumor suppressor genes, including the disease-specific critical gene <i>SMAD4</i>. Collectively, our post-GWAS solution establishes a foundation for discovering potential drug targets. PIG guides the future exploration of therapeutic possibilities, such as repurposing drugs like arsenic trioxide and employing mRNA therapeutics delivered via lipid nanoparticles, to advance translational medicine strategies for glaucoma—the second leading cause of irreversible blindness, particularly for patients also with pancreatic disease.</p>

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Glaucoma Drug Target Prioritisation Informs Disease-specific Therapeutic Potentials of Targeting SMAD4

  • 期刊论文

  • 发表日期：

    2026年6月22日

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  • Chaohui Bao,
  • Tingting Tan,
  • Yisheng Yang,
  • Chenxu Gao,
  • Kaiwen Liu,
  • Chang Lu,
  • Rulin Guo,
  • Zheng Wang,
  • Jiantao Shi,
  • Jinchen Li,
  • Ming Ni,
  • Hai Fang,
  • Huaxin Song

摘要

Genome-wide association studies (GWAS) identify genetic associations for glaucoma, particularly its subtype, open-angle glaucoma (OAG). Translating these disease-genetic associations into therapeutic targets and potential drugs, however, remains a challenge. We propose to address this post-GWAS challenge with the priority index solution to glaucoma (PIG), which leverages genetic and network evidence for drug target prioritisation. PIG not only recovers clinical proof-of-concept targets for OAG but also supports integrated analysis for pathway crosstalk identification. The latter further enables crosstalk-based therapeutic discovery: removal analysis to identify key nodes with the crosstalk; drug repurposing analysis to identify candidate drugs; and construction of a prioritisation map across diseases to reveal disease-specific targeting potential for OAG. These multifaceted functionalities provide therapeutic insights into targeting the FoxO signaling pathway, which includes tumor suppressor genes, including the disease-specific critical gene SMAD4. Collectively, our post-GWAS solution establishes a foundation for discovering potential drug targets. PIG guides the future exploration of therapeutic possibilities, such as repurposing drugs like arsenic trioxide and employing mRNA therapeutics delivered via lipid nanoparticles, to advance translational medicine strategies for glaucoma—the second leading cause of irreversible blindness, particularly for patients also with pancreatic disease.