Examining the genetic regulation of A-to-I editing and mediation of Alzheimer's disease

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Project Summary Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, affecting approximately 6 million adults in the United States, for which there is no cure or treatments which effectively slow progression of the disease. Genome-wide association studies (GWAS) have illuminated 75 loci associated with AD, but the causal variants underlying the disease-associations remain to be identified, along with the genes or pathways through which they act to regulate higher-order phenotypes. The integration of genomics with transcriptomics can inform the influence of common genetic variation on molecular phenotypes consequential to cellular function. My lab has shown that AD susceptibility loci are enriched for genetic variants which alter RNA levels and/or splicing, and these variants often lie in cis-regulatory elements enriched in myeloid cells. However, causal variants or genes remain elusive for most loci associated with AD. This proposal will contribute a valuable resource for research seeking to describe causal variants at GWAS risk loci and connect them to altered cellular function. Intricate pre- and post-transcriptional processing of awards vast functional diversity to RNA molecules, and among the most abundant post-transcriptional modifications is adenosine-to-inosine (A-to-I) RNA editing. In protein-coding regions, these base-specific changes “recode” amino acid sequences, and in non-coding regions, A-to-I editing fine-tunes genes by influencing the splicing, stability, and subcellular localization of RNA transcripts, along with their ability to bind micro-RNAs (miRNAs). Disrupted RNA editing activity has been widely reported in AD patients, but whether this is a consequence of the disease, or cause is not clear. This proposal will address the contributions of RNA editing to AD pathophysiology by testing the hypothesis that AD-associated genetic variants modulate A-to-I editing. I will use quantitative trait loci (QTL) mapping to relate common genetic variation to level of RNA editing at A-to-I events genome-wide in the brain and myeloid cells. Then, I will apply advanced statistical approaches to determine whether the genetic regulators of A-to-I editing reside in GWAS risk loci for AD. Importantly, I will implement appropriate methodology probing mediation, to parse bona fide causal gene regulatory pathways apart from pleiotropy or spurious effects of genetic associations. By prioritizing A-to-I editing sites which are subject to tight genetic regulation and resolving the molecular and cellular processes they help to orchestrate, the results from this work lay critical foundation for follow-up functional studies which can harness the power of RNA based therapeutics to develop treatments for AD.