Abstract: BACKGROUND: Spinal osteoarthritis is a common degenerative spinal disease that severely affects quality of life of patients, but its exact molecular mechanism remains unclear. 
OBJECTIVE: To identify plasma proteins related to spinal osteoarthritis through Mendelian randomization analysis and provide a reference for finding new potential therapeutic targets in this disease field.
METHODS: Protein data were obtained from the deCODE Genetics database (A total of 35 559 Icelandic individuals were included, and genetic association information of 4 907 plasma proteins was detected, https://www.decode.com/summarydata/). Spinal osteoarthritis data were obtained from the Osteoarthritis Genetics Consortium (A total of 826 690 samples are available for free download via https://msk.hugeamp.org/downloads.html). All data are open source and comply with ethical requirements. Wald ratio or inverse variance weighting was used to assess the causal relationship between 4 907 plasma proteins and spinal osteoarthritis, with Bonferroni correction applied to the P-values. In addition, Steiger directional test was performed to exclude reverse causality; colocalization analysis was performed to exclude linkage disequilibrium; phenotype scanning was performed to exclude horizontal pleiotropy, and external validation was performed to exclude accidental findings. Finally, the online analysis tool Enrichr was used to screen small-molecule compounds targeting causal proteins. Molecular docking was performed on the top-ranked compounds to predict their binding patterns and energies with proteins, thus identifying the most stable and potential binding modes.
RESULTS AND CONCLUSION: (1) Among 4 907 proteins, 1 878 significant protein quantitative trait locus were screened from 1 553 proteins. After Mendelian randomization analysis, four proteins were identified to have a strong causal relationship with spinal osteoarthritis, namely monocytic CD14, interleukin-12 beta subunit, hepatocyte growth factor-like protein, and Semaphorin-4A. Among them, interleukin-12 beta subunit was negatively correlated with spinal osteoarthritis, while the remaining proteins were positively correlated with spinal osteoarthritis. (2) Additionally, drug prediction results showed that tesmilifene targeting CD14, montelukast targeting interleukin-12 beta subunit, naphthalenamine targeting hepatocyte growth factor-like protein, and lycorine targeting semaphorin-4A all demonstrated good binding affinity in molecular docking, with minimum binding energies below -6.0 kJ/mol. (3) Comprehensive analysis suggest that these four plasma proteins may serve as potential biomarkers or drug development targets for clinical screening, prevention, and intervention of spinal osteoarthritis, and also provide theoretical basis and reference value for related studies in the Chinese population.

Key words: plasma proteins, spinal osteoarthritis, Mendelian randomization, Bayesian colocalization, phenotype scanning, molecular docking