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

INTRODUCTION: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.