Abstract
The two-sample Mendelian randomization (MR) study revealed a causal association of plasma proteins with osteoporosis (OP) and osteoarthritis (OA). Bone mineral density (BMD) is the gold standard for the clinical assessment of OP. Recent studies have shown that plasma proteins play an essential role in the regulation of bone development. However, the causal association of plasma proteins with BMD and OA remains unclear. We estimated the effects of 2889 plasma proteins on 2 BMD phenotypes and 6 OA phenotypes using two-sample MR analysis based on the genome-wide association study summary statistics. Then, we performed sensitivity analysis and reverse-direction MR analysis to evaluate the robustness of the MR analysis results, followed by gene ontology (GO) enrichment analysis and KEGG pathway analysis to explore the functional relevance of the identified plasma proteins. Overall, we observed a total of 257 protein-estimated heel BMD associations, 17 protein-total-body BMD associations, 2 protein-all-OA associations, and 2 protein-knee-OA associations at PFDR < 0.05. Reverse-direction MR analysis demonstrated that there was little evidence of the causal association of BMD and OA with plasma proteins. GO enrichment analysis and KEGG pathway analysis identified multiple pathways, which may be involved in the development of OP and OA. Our findings recognized plasma proteins that could be used to regulate changes in OP and OA, thus, providing new insights into protein-mediated mechanisms of bone development.
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Data Availability
Data generated or analyzed during this study are included in this published article or in the data repositories listed in References. Some datasets generated during and/or analyzed during the current study are not publicly accessible but are available from the corresponding author on reasonable request.
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Acknowledgements
We are grateful to all studies that released GWAS summary statistics for use in this study.
Funding
YFP was partially supported by the funding from the national natural science foundation of China (32170670) and a project funded by the Priority Academic Program Development (PAPD) of Jiangsu higher education institutions. The numerical calculations in this manuscript have been done on the supercomputing system of the National Supercomputing Center in Changsha.
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YFP and LZ: designed the study. BXH and YFP: collected the data. BXH and YFP: analyzed the data. SSY, YH, QX, QGZ, XLM, JJN, and BXH: performed the literature search. BXH: drafted the early version of the manuscript. YFP and LZ: jointly supervised the study. All authors were involved in writing the paper and had final approval of the submitted and published versions.
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Bai-Xue Han, Shan-Shan Yan, Yu Han, Qian Xu, Qi-Gang Zhao, Xin-Ling Ma, Jing-Jing Ni, Lei Zhang, and Yu-Fang Pei declare they have no conflict of interest.
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Han, BX., Yan, SS., Yu Han et al. Causal Effects of Plasma Proteome on Osteoporosis and Osteoarthritis. Calcif Tissue Int 112, 350–358 (2023). https://doi.org/10.1007/s00223-022-01049-w
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DOI: https://doi.org/10.1007/s00223-022-01049-w