Integrating Mendelian Randomization with Single-cell Sequencing Data Reveals the Causal Effect and Related Mechanisms of Smoking on Parkinson's Disease

Abstract Introduction Smoking (nicotine) has been reported to possibly be neuroprotective and conducive to patients with early Parkinson’s disease (PD). However, the causal effect of smoking on PD and the molecular mechanisms of smoking-related genes (SRGs) are vague. Aims and Methods First, genome-wide association study summary data on smoking (ukb-b-6244) and PD (ieu-b-7) were retrieved from the Integrative Epidemiology Unit OpenGWAS database for Mendelian randomization (MR) analysis. Sensitivity analyses were performed to validate the results of the MR analyses. Subsequently, a differential analysis of PD patients and controls was performed to identify differentially expressed SRGs (DE-SRGs). Finally, the expression of DE-SRGs was analyzed in annotated cell types. Results The MR analysis revealed that smoking was a protective factor causally related to PD (p = .008, odds ratio = 0.288). Furthermore, a total of five DE-SRGs enriched in Toll-like receptor signaling pathways were identified in GSE7621 dataset. Regarding the single-cell analysis of the GSE184950 dataset, a total of nine cell types were annotated. The expression of LRRN1 in oligodendrocyte progenitor cells and oligodendrocytes, respectively, differed significantly between PD patients and controls. Conclusions Our study supported a causal relationship between smoking and PD and found that five SRGs (MAPK8IP1, LRRN1, LINC00324, HIST1H2BK, and YOD1) enriched in Toll-like receptor signaling pathways might be beneficial in PD. In addition, single-cell sequencing indicated that four SRGs were differentially expressed in different cell types. All four genes except MAPK8IP1 were significantly correlated with the 10 genes calculated by scPagwas. Thus, this evidence provides a theoretical basis for further research on the effect of nicotine (smoking) on PD. Implications In search of explore the potential etiology and pathogenesis of Parkinson’s disease, this study combined MR analysis, transcriptomics, and single-cell sequencing analysis to explore the association between exposure factors and Parkinson’s disease, observe and confirm the relationship and mechanism between the two from the perspective of genetics, and provide more reliable evidence for causal inference.