Casual association between CX3CL1/CX3CR1 and Parkinson's Disease: A Mendelian randomization and Colocalization study

Abstract

Abstract Background: The association between CX3CL1/CX3CR1 and Parkinson’s Disease (PD) has been minimally explored in pre-clinical and observational studies. However, evidence from animal studies indicates that CX3CL1/CX3CR1 can exert both neuroprotective and neurotoxic effects on PD. Given the scarcity of clinical studies,our objective is to explore the causality between CX3CL1/CX3CR1 and PD using a two-sample Mendelian randomization approach in conjunction with colocalization analysis.. Methods: We constructed a bidirectional two-sample Mendelian randomization (MR) to assess the causal link between CX3CL1/CX3CR1 and PD, employing genetic variants as instrumental variables, we intend to analyze the most extensive genome-wide association study data available for PD as the outcome measure. The primary outcome was derived using the inverse variance weighted (IVW) method .Additional analyses, including Mendelian randomization Egger regression, weighted median, and mode approaches, were utilized to reinforce the robustness of our findings. The debiased inverse variance weighted estimator was introduced to adjust for potential weak instrument bias. To robustly validate our findings, we carried out a comprehensive series of sensitivity analyses. Results: Our study examined 33,674 cases of PD and 449,056 controls, revealing three key findings. We discovered that for every one-standard deviation (SD) increase in plasma CX3CR1 levels in monocytes, there was a 10.3% decrease in PD risk (IVW; OR = 0.897, 95%CI = 0.831 - 0.968, P_adj = 0.012). Furthermore, a one-SD increase in CX3CR1 levels on CD14+ CD16+ monocytes resulted in an 8.9% lower PD risk (IVW; OR = 0.911, 95% CI = 0.863 - 0.962, P_adj = 0.006), and a similar increase on CD14+ CD16- monocytes led to a 9.3% reduction in risk (IVW; OR = 0.907, 95% CI = 0.850 - 0.967, P_adj = 0.010). Through comprehensive sensitivity analyses, the reliability of these results was confirmed. Additionally, our colocalization analysis identified a significant association of the lead SNP rs6658353 with CX3CR1 expression in monocytes. This SNP also showed significant colocalization with CX3CR1 in both CD14+ CD16+ and CD14+ CD16- subsets, indicating its role in regulating CX3CR1 expression. Conclusion: This study suggests a potential link between higher peripheral expression of CX3CR1 on monocytes and a reduced risk of PD. Specifically, increased levels of plasma CX3CR1, as well as its expression on CD14+ CD16+ and CD14+ CD16- monocytes, were associated with a decreased PD risk. These results lend support to the hypothesis that CX3CR1 plays a crucial role in the causal pathway to PD.