Transcriptomic analysis reveals associations of blood-based A-to-I editing with Parkinson's disease

Background: Adenosine-to-inosine (A-to-I) editing is the most common type of RNA editing in humans and the role of A-to-I RNA editing remains unclear in Parkinson's disease (PD).

Objective: We aimed to explore the potential causal association between A-to-I editing and PD, and to assess whether changes in A-to-I editing were associated with cognitive progression in PD.

Methods: The RNA-seq data from 380 PD patients and 178 healthy controls in the Parkinson's Progression Marker Initiative cohort was used to quantify A-to-I editing sites. We performed cis-RNA editing quantitative trait loci analysis and a two-sample Mendelian Randomization (MR) study by integrating genome-wide association studies to infer the potential causality between A-to-I editing and PD pathogenesis. The potential causal A-to-I editing sites were further confirmed by Summary-data-based MR analysis. Spearman's correlation analysis was performed to characterize the association between longitudinal A-to-I editing and cognitive progression in patients with PD.

Results: We identified 17 potential causal A-to-I editing sites for PD and indicated that genetic risk variants may contribute to the risk of PD through A-to-I editing. These A-to-I editing sites were located in genes NCOR1, KANSL1 and BST1. Moreover, we observed 57 sites whose longitudinal A-to-I editing levels correlated with cognitive progression in PD.

Conclusions: We found potential causal A-to-I editing sites for PD onset and longitudinal changes of A-to-I editing were associated with cognitive progression in PD. We anticipate this study will provide new biological insights and drive the discovery of the epitranscriptomic role underlying Parkinson's disease.