Abstract
This study, using a two-sample and two-step Mendelian randomization (MR) approach, reveals a causal relationship between specific circulating plasma proteins and osteoporosis risk, and further identifies key deCODE Genetics plasma proteins (measured in a different population and using an independent proteomic platform) mediating the effects of upstream UKB plasma proteins.Notably, proteins such as NT5C, GREM1, BOLA1, and CCL19 were found to partially mediate the effects of upstream UKB plasma proteins on bone health. These findings shed light on a multi-tiered protein regulatory network underlying osteoporosis and provide potential targets for therapeutic intervention. INTRODUCTION: Osteoporosis is a multifactorial skeletal disorder characterized by reduced bone mineral density (BMD) and increased fracture risk. Circulating plasma proteins are emerging as potential mediators of bone metabolism, yet their causal roles and inter-protein regulatory mechanisms in osteoporosis remain unclear. METHODS: We conducted a comprehensive two-sample MR study using protein quantitative trait loci (pQTL) data from the UK Biobank Pharma Proteomics Project (UKB; n = 54,219) and deCODE Genetics (n = 35,559) to investigate the causal effects of 2,923 and 4,907 plasma proteins, respectively, on osteoporosis risk (10,461 cases, 473,264 controls from FinnGen). A two-step MR framework was further applied to assess whether deCODE plasma proteins mediated the effects of UKB proteins on osteoporosis. Causal estimates were derived using inverse variance weighted (IVW) as the primary method, with additional sensitivity analyses including MR-Egger, MR-PRESSO, and leave-one-out tests. RESULTS: Eighty-three UKB plasma proteins were causally associated with osteoporosis (FDR < 0.01), including known regulators (e.g.,GALNT3, IL18, IL7R) and novel candidates (e.g., NUDT2,SMOC2). Seven deCODE proteins also showed significant effects, includingGREM1, PRRG4, NT5C, and CCL19. Two-step MR analyses revealed that NT5C, BOLA1, GREM1, and CCL19 significantly mediated the effects of upstream UKB proteins on osteoporosis, with mediation proportions ranging from 3.93% to 17.95%, supporting multi-tiered protein-to-protein causal pathways. CONCLUSION: This study systematically identifies circulating plasma proteins with causal effects on osteoporosis and highlights key intermediaries mediating these effects. Our findings provide novel insights into protein-mediated regulatory networks in bone metabolism and offer promising targets for future therapeutic interventions.