NUDT2 and A proteome-wide causal map of plasma proteins in osteoporosis.

Authors

Zhen Wang, Sixu Chen, Junjie Luo, Zhengbo Liu, Jing Wen, Binyang Feng, Wen-Hao Ye, Jian-Chao Ma, Zhenyue Chen, Zhen Li, Zhenwen Yang, Junxiang Qiu, Zhong-Kai Cui

Published in

Journal of advanced research. Aug 08, 2026. Epub Aug 08, 2026.

Abstract

Pharmacological targets supported by genetic evidence demonstrate significantly higher success rates in clinical development. Osteoporosis (OP) represents a major global health burden; however, the causal plasma proteome underlying OP remains largely unexplored, limiting the discovery of effective circulating biomarkers and therapeutic agents.
This study aimed to conduct a comprehensive proteome-wide analysis to construct a causal map of plasma proteins for OP and to identify high-confidence therapeutic targets with translational potential.
We performed a proteome-wide Mendelian randomization (PW-MR) analysis by integrating large-scale GWAS meta-analysis data (18,008 OP cases and 928,650 controls) with cis-acting protein quantitative trait loci (pQTLs) derived from the deCODE and UKB-PPP cohorts. To ensure robustness, we employed orthogonal validation approaches, including colocalization analyses, summary data-based Mendelian randomization (SMR), and single-cell transcriptomic mapping.
We identified 144 plasma proteins causally associated with OP, encompassing two novel susceptibility loci (HOXC5 and HBQ1) and five previously unreported candidates (NUDT2, NUB1, TNFSF8, UNG, and MXRA8). Notably, single-cell mapping revealed that NUDT2 is specifically enriched in osteoprogenitor cells, distinct from other identified targets.
These findings delineate the first causal blueprint of the OP plasma proteome. NUDT2 is highlighted as a plausible metabolic regulator of bone formation. Collectively, this study provides a valuable resource for precision diagnostics and accelerates the development of novel therapeutics for osteoporosis.

PMID:
42570691
Bibliographic data and abstract were imported from PubMed on 09 Aug 2026.

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