Objective:

To investigate the contribution of genetically predicted B-cell gene expression to Parkinson’s disease risk and to identify potential therapeutic targets through computational analysis.

Key Findings:

• Prioritized eight high-confidence MR causal genes: five risk-increasing (CD74, HLA-DRB1, IL2RA, BLK, BANK1) and three protective (CR1, PTPN22, FCRL3), linking findings to methods.
• Exploratory pseudobulk analysis indicated early-change genes detectable in early PD stages, suggesting potential biomarkers.
• Subpopulation analysis revealed enrichment in Naive B and Atypical B cells, highlighting their roles in PD.
• CellChat analysis suggested increased MIF signaling pathway communication in later PD stages, indicating a shift in immune response.
• Molecular docking indicated structural plausibility for interactions with selected small molecules, supporting therapeutic exploration.

Interpretation:

The findings suggest that genetically influenced B-cell gene expression may contribute to peripheral immune dysregulation in Parkinson’s disease, with implications for future therapeutic strategies.

Limitations:

• Results are hypothesis-generating and require experimental and clinical validation; future studies should aim to establish causality.
• The study does not establish direct causality between B-cell changes and PD risk, highlighting the need for longitudinal studies.

Conclusion:

CD74, IL2RA, and CR1 are nominated as candidate therapeutic targets for future validation, emphasizing the need for further research to confirm these findings.