Peripheral immune cell-specific genes in Parkinson’s disease uncovered by multi-omics with therapeutic implications

Parkinson’s disease (PD) is a complex neurodegenerative disorder with growing evidence suggests peripheral immunity plays a role in its pathogenesis. However, the specific peripheral immune cell types and gene expression profiles associated with PD remain unclear. In this study, we integrated single-cell expression quantitative trait loci (sc-eQTL) data from 14 immune cell types in the OneK1K cohort with large-scale genome-wide association study (GWAS) data for PD. Using Mendelian randomization (MR) and Bayesian colocalization analyses, we identified 28 immune-cell-specific eGenes with significant associations to PD risk, among which 24 showed strong or moderate evidence of shared genetic signals. Notable candidates included FDFT1, ARSA, CTSB, and HLA-DQA1, each displaying cell-type-specific associations in CD4+ T cells, CD8+ T cells, B cells, and monocytes. Replication using an independent sc-eQTL dataset from the DICE project confirmed consistent findings for several eGenes. Additional validation through peripheral blood single-cell RNA sequencing (scRNA-seq) revealed distinct expression patterns and significant changes in PD patients. Phenome-wide association studies (PheWAS) showed multiple associations with immune-related traits and minimal associations with unrelated traits, indicating a favorable safety profile for therapeutic targeting. Drug repurposing analysis identified several candidate compounds, including felodipine, amodiaquine, alprazolam, and tetrandrine, some of which are predicted to cross the blood-brain barrier. Molecular docking simulations further supported strong binding interactions between these compounds and PD-associated targets such as CTSB and ARSA. This integrative approach highlights key immune-cell-specific genes involved in PD and proposes several repurposable drugs with central nervous system potential, paving the way for more targeted therapeutic strategies.