To determine whether RNA editing quantitative trait loci (edQTLs) explain RNA editing differences between Alzheimer disease (AD) cases and controls in African-American (AA) and Non-Hispanic White (NHW) populations.

We have shown that RNA editing, the post-transcriptional modification of RNA bases, is altered between AD cases and controls in both AA and NHW (Gardner, 2019). However, it is unknown whether DNA variants that influence the rates of RNA editing, referred as edQTLs (similar to eQTLs), are contributing to these differences in both populations. 

We performed edQTL analysis using RNAseq from peripheral blood of 216 AD cases (105 AA, 111 NHW) and 212 cognitively intact controls (105 AA, 107 NHW), all over age 65. FastQTL was used to map edQTLs using genotyping data from the Infinium GSA with editing rates calculated with REDItools, adjusting for covariates.  Associations with an FDR corrected p-value less than 1% were considered significant.

We identified 14,022 (AA) and 9,174 (NHW) edQTLs. Of these, 104 in AA and 46 in NHW were edQTLs for sites differentially edited between AD cases and controls. Among the edQTLs associated with differentially edited sites, 31 were in linkage disequilibrium (r²>=0.5) with an AD-associated region defined by the European-ancestry genome-wide association study from the International Genomics of Alzheimer’s Project (Kunkle, 2019). These edQTLs were strongly enriched amongst NHW (23 NHW only, 8 both, 0 AA only) and included the SORL1, SLC24A4, SPI1, and HLA-DRB1 gene loci.

Our data support our hypothesis that edQTLs contribute to RNA editing differences between AD cases and controls in both AA and NHW and thus could be a mechanism for the functional effect of AD risk variants. However, edQTLs in regions associated with AD in European ancestry did not generalize across ancestries, underscoring the crucial need for genetic studies in multi-ethnic populations to understand mechanisms of AD risk.