CPNE1 modulates Parkinson's disease risk through peripheral immune cell function: a cross-tissue and single-cell causal inference study.

It has been increasingly recognized that, to a significant extent, the peripheral immune system is playing a role in the etiology of Parkinson’s disease (PD). It has been reported recently that there may be multiple types of genetic susceptibility factors influencing the risk of PD through alterations in the functions of particular immune cells; at present, the precise mechanisms involved remain unclear. Based on a multi-dimensional causality inference model that included data from genome-wide association studies (GWAS), expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL) and single-cell eQTL (sc-eQTL), we performed both cross-tissue Mendelian randomization (MR) analysis and immune cell-specific MR analysis to investigate the association between genetic risk factors and peripheral immune functions based on individuals with PD. We found that the genetic prediction of CPNE1 expression had a negative association with PD risk in whole blood, substantia nigra and several immune cell types. The results support a possible protective relationship between CPNE1 and PD risk; however, the subsequent biological mechanism remains unclear. Genetically predicted CPNE1 expression showed a significant association with lower PD risk at the level of immune cells in nine different subtypes: T cells, monocytes, natural killer cells and so on. In addition, the exploratory immune-infiltration analysis of peripheral-blood transcriptomics data showed that there was a positive correlation of CPNE1 expression with the inferred number of regulatory T-cells; therefore, this result requires confirmation in subsequent studies. Our results suggest that CPNE1 could be a candidate factor for the reduced PD risk in blood, substantia nigra and several immune cell subsets. The above results suggest that peripheral immune regulation is likely associated with the link between CPNE1-relevant pathways and PD; however, it cannot determine the intermediate steps linking peripheral immune effects to neuroprotection in the brain.