A plasma proteome-mediated Mendelian randomization study reveals the impact of rheumatoid arthritis on mental disorders in a European population

Objective: This study aimed to evaluate the potential mediating role of the plasma proteome in the association between rheumatoid arthritis (RA) and mental disorders. Methods: A two-sample, two-step mediation Mendelian randomization (MR) approach was used to investigate the causal relationship between RA and mental disorders and the role of plasma proteins in these associations. Sensitivity analyses were conducted to validate the MR results. Results: Through MR analysis, we identified associations between RA subtypes (seropositive RA [SPRA] and seronegative RA [SNRA]) and various mental disorders, including bipolar disorder (BD), anxiety disorder (AD), and hoarding disorder (HD). Significant positive correlations were observed between RA and AD (odds ratio [OR]: 1.1547; P = 0.0304), SPRA and HD (OR: 1.0138; P = 0.0464), and SNRA and BD (OR: 1.0530; P = 0.0382). Protein association analysis identified 167, 71, and 95 plasma proteins significantly associated with BD, AD, and HD, respectively. After sensitivity testing and false discovery rate (FDR) correction, 15 proteins were significantly associated with BD. Mediation analysis indicated that EF-hand calcium-binding domain-containing protein 14 (EFCAB14) played a major mediating role in the pathway between SNRA and BD, accounting for 45.8 % of the effect followed by Cadherin-related family member 1 (CDHR1), which accounted for 23.2 %. Conclusion: This study highlighted the significant role of RA in mental disorder development, with plasma proteins partially mediating this effect and lays the groundwork for future diagnostic biomarkers and intervention strategies.