RNA editing alterations in a multi-ethnic Alzheimer disease cohort converge on immune and endocytic molecular pathways.

TitleRNA editing alterations in a multi-ethnic Alzheimer disease cohort converge on immune and endocytic molecular pathways.
Publication TypeJournal Article
Year of Publication2019
AuthorsGardner OK, Wang L, Van Booven D, Whitehead PL, Hamilton-Nelson KL, Adams LD, Starks TD, Hofmann NK, Vance JM, Cuccaro ML, Martin ER, Byrd GS, Haines JL, Bush WS, Beecham GW, Pericak-Vance MA, Griswold AJ
JournalHum Mol Genet
Date Published09/2019
KeywordsAlleles, Alzheimer Disease, Computational Biology, Disease Susceptibility, Gene Expression Profiling, Gene Expression Regulation, Gene Ontology, Genetic Predisposition to Disease, Genotype, Humans, Molecular Sequence Annotation, RNA Editing, Signal Transduction, Transcriptome

Little is known about the post-transcriptional mechanisms that modulate the genetic effects in the molecular pathways underlying Alzheimer disease (AD), and even less is known about how these changes might differ across diverse populations. RNA editing, the process that alters individual bases of RNA, may contribute to AD pathogenesis due to its roles in neuronal development and immune regulation. Here, we pursued one of the first transcriptome-wide RNA editing studies in AD by examining RNA sequencing data from individuals of both African-American (AA) and non-Hispanic White (NHW) ethnicities. Whole transcriptome RNA sequencing and RNA editing analysis were performed on peripheral blood specimens from 216 AD cases (105 AA, 111 NHW) and 212 gender matched controls (105 AA, 107 NHW). 449 positions in 254 genes and 723 positions in 371 genes were differentially edited in AA and NHW, respectively. While most differentially edited sites localized to different genes in AA and NHW populations, these events converged on the same pathways across both ethnicities, especially endocytic and inflammatory response pathways. Furthermore, these differentially edited sites were preferentially predicted to disrupt miRNA binding and induce nonsynonymous coding changes in genes previously associated with AD in molecular studies, including PAFAH1B2 and HNRNPA1. These findings suggest RNA editing is an important post-transcriptional regulatory program in AD pathogenesis.

Alternate JournalHum. Mol. Genet.
PubMed ID31162550
PubMed Central IDPMC6737295
Grant ListP30 AG049638 / AG / NIA NIH HHS / United States