Genetic control of RNA editing in Neurodegenerative disease

Abstract

A-to-I RNA editing diversifies human transcriptome to confer its functional effects on the downstream genes or regulations, potentially involving in neurodegenerative pathogenesis. Its variabilities are attributed to multiple regulators, including the key factor of genetic variant. To comprehensively investigate the potentials of neurodegenerative disease-susceptibility variants from the view of A-to-I RNA editing, we analyzed matched genetic and transcriptomic data of 1,596 samples across nine brain tissues and whole blood from two large consortiums, Accelerating Medicines Partnership - Alzheimer's Disease (AMP-AD) and Parkinson's Progression Markers Initiative (PPMI). The large-scale and genome-wide identification of 95,637 RNA editing quantitative trait loci revealed the preferred genetic effects on adjacent editing events. Furthermore, to explore the underlying mechanisms of the genetic controls of A-to-I RNA editing, several top RNA binding proteins were pointed out, such as EIF4A3, U2AF2, NOP58, FBL, NOP56, and DHX9, since their regulations on multiple RNA editing events probably interfered by these genetic variants. Moreover, these variants may also contribute to the variability of other molecular phenotypes associated with RNA editing, including the functions of four proteins, expressions of 148 genes, and splicing of 417 events. All the analyses results shown in NeuroEdQTL (https://relab.xidian.edu.cn/NeuroEdQTL/) constituted a unique resource for the understanding of neurodegenerative pathogenesis from genotypes to phenotypes related to A-to-I RNA editing.

The Potential Regulation of A-to-I RNA editing on Genes in Parkinson’s Disease

“…To improve the understanding of these biomarkers, it is better to annotate their potential up-regulators. Specifically, for the three editing examples introduced in detail, we discovered the main editing enzyme and genetic variants [60] which may affect these A-to-I RNA editing events ( Figure S3 ). The analyses could link the DNA mutations or ADAR , A-to-I RNA editing events, miRNA regulations, and gene expressions together, to explain the potentially regulatory processes in neurodegenerative pathogenesis and be helpful for the treatment of the diseases.…”