The goal of this project is to functionally annotate genetic variants in post-transcriptional regulation of RNA expression, which extends and complements the current focus of ENCODE data analysis. In this supplement, we will systematically identify genetic variants that affect post- transcriptional regulation in Alzheimer?s disease (AD), complementary to work in the currently funded project. Recently, tremendous success has been achieved in constructing a catalog of genetic variants in AD genomes. The next great challenge is to identify functional variants and elucidate their potential roles in biological and disease processes. To this end, research efforts have been directed to studying variants located in protein-coding, promoter, and splice site regions due to their apparent impacts on gene expression. However, many of the newly identified disease-associated variants reside in other non-coding regions, such as introns, that may confer regulatory function to the related gene. The mechanisms of these variants have been hard to decipher. It is expected that many of them may function at the post-transcriptional level, thus affecting mRNA expression. However, how to accurately identify such functional genetic variants remains a key question for AD research. To address this question, we will develop novel high-throughput assays, combined with computational analysis and predictions, to capture functional AD-relevant variants in post-transcriptional regulation. This work will allow a previously unattained level of understanding of genetic variants in post-transcriptional regulation in AD and provide new means to tackle the imperative task of functional annotations of genetic variants.
Post-transcriptional regulation can significantly alter gene expression and contribute to human diseases. The proposed research aims to identify functional genetic variants in post- transcriptional regulation of mRNA expression in Alzheimer?s disease. This work will provide mechanistic basis for how genetic variations may contribute to the disease, such that future interventions can target specific genes therapeutically.
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