Abstract
Alzheimer disease (AD) is the most common form of dementia and the sixth leading cause of death in the United States. Genetic studies have implicated several biological processes in the pathogenesis of Alzheimer Disease (AD) including immune response, regulation of endocytosis, and inflammation, but little is known about the mechanisms by which these processes are altered. RNA editing, the post-transcriptional modification of individual bases, is an epigenetic mechanism that plays a vital role in neuronal development and immune regulation, and dysregulated RNA editing has been observed in neurological diseases including AD. In this study, I pursued a transcriptome-wide study of RNA editing in peripheral blood specimens from 216 AD cases (105 AA, 111 NHW) and 212 age matched controls (105 AA, 107 NHW). I found that RNA editing in whole blood from AD cases changed in genes associated with immunity and endocytosis. I also found that the specific loci of differential editing varied between African American (AA) and non-Hispanic White (NHW) populations but that the pathways affected were the same across both ethnicities. Because RNA editing rates are known to be influenced by population-specific genetic variants, I followed up this differential RNA editing experiment with an editing quantitative trait loci (edQTL) analysis to identify shared and population-specific genetic variants associated with differential RNA editing in AA and NHW AD populations. I then compiled our analytical methods into a set of R packages, which are now available on github, to make RNA editing studies more accessible to the broader research community and to facilitate potential translational applications. I further applied these analytical methods to an additional dataset from a Puerto Rican AD case-control cohort. With this work, I characterized AD-associated changes of RNA editing in a multi-ethnic cohort, as well as the genetic architecture underlying these changes, and developed novel tools to facilitate these analyses.