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Circulating proteins and bone mineral density: A Proteome-Wide Mendelian Randomization Study.
Tianyi Wang1,2, Liu Liu1,3, Ruiying Han1,2
1State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, 3rd Section of Ren Min Nan Rd., Chengdu, 610041, China.
Current Medicinal Chemistry
|September 5, 2025
Summary
This study identifies novel genetic targets for bone mineral density (BMD) using proteome-wide Mendelian randomization, offering new avenues for osteoporosis drug development and repurposing.
Area of Science:
- Genetics and Genomics
- Pharmacology and Drug Development
- Bone Biology and Osteoporosis Research
Background:
- Current osteoporosis medications have limitations in efficacy.
- Identifying novel druggable genetic targets is crucial for developing improved osteoporosis treatments.
- Mendelian randomization (MR) offers a robust method to identify causal genetic associations, overcoming limitations of traditional observational studies.
Purpose of the Study:
- To identify novel, druggable genetic targets for bone mineral density (BMD) using a large-scale proteome-wide Mendelian randomization (pQTL) approach.
- To validate identified targets through expression quantitative trait loci (eQTL) analysis and functional experiments.
- To explore potential for drug repurposing and development for osteoporosis.
Main Methods:
- Employed two-sample Mendelian randomization (MR) utilizing protein quantitative trait loci (pQTL) and expression quantitative trait loci (eQTL) data.
- Meta-analyzed pQTL evidence across large datasets (deCODE, UKB-PPP) for six bone mineral density (BMD) sites.
- Conducted MR sensitivity tests, assessed druggability, and performed functional analyses including transcriptomics and OVX experiments.
Main Results:
- Identified 16 prioritized targets from 5,928 pQTLs, with four novel key druggable targets for BMD: LYN, CHAD, TNFRSF19, and TGFBI.
- Validated previously suggested targets RSPO3 and SMOC2.
- Functional analysis revealed elevated TNFRSF19 and TGFBI expression negatively correlated with BMD.
Conclusions:
- This large-scale Proteome-Wide MR study successfully identified novel genetic targets for BMD at both transcriptional and translational levels.
- The findings provide new therapeutic insights and present promising prospects for osteoporosis drug repurposing and development.
- The identified targets (CHAD, LYN, TGFBI, TNFRSF19) represent significant advancements in understanding BMD regulation.
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