Meta-analysis of genetic regulation of RNA editing in the human brain identifies new genes underlying neurological disease

Abstract

Adenosine-to-inosine (A-to-I) RNA editing is among the most abundant post-transcriptional modifications, whose role in homeostasis and disease of the central nervous system (CNS) has been extensively reported. Regulation of A-to-I editing by cis-acting genetic variants (edQTLs) is understudied, especially in the brain. As a part of the BigBrain Project (n=4,471 individuals), which represents a >10-fold increase in sample size from previous edQTL studies, we harmonized A-to-I sites across datasets to perform a meta-analysis that identified 38,731 edQTLs in 3,554 genes. Integrating other QTL summary statistics from BigBrain, we show edQTLs in 3 untranslated regions (3UTR) are more likely to share a genetic effect with gene expression or splicing. Using colocalization analysis, we identify 24 GWAS loci for neurological disorders explained by edQTLs alone, or in concert with other molecular QTLs. This study represents a valuable resource to the field of RNA editing and neurogenetics.