Systematic analysis of functional 3’ UTR genetic variants and their relevance to Alzheimer’s Disease

Project Summary The goal of this project is to identify and characterize functional 3’ UTR genetic variants that alter post-transcriptional regulation of mRNA abundance, with a focus on variants relevant to Alzheimer’s disease (AD). Recently, an increasing number of genetic variants have been cataloged that confer risks to human diseases, including AD. However, it remains a great challenge to identify causal variants and elucidate their potential function relevant to disease pathogenesis and progression. Compared to the progress in pinpointing genetic variants that alter transcriptional regulation or protein-coding sequences, how genetic variants may affect post-transcriptional processes is poorly understood. Many of the newly identified AD-associated variants reside in non-coding regions, such as introns and 3’ UTRs, that may confer regulatory function to the related gene, especially at the level of post-transcriptional regulation. In particular, the 3’ UTRs of human genes are enriched with many cis-regulatory elements recognized by trans-factors, such as RNA-binding proteins (RBPs). Together, these cis-elements and trans-factors dictate many aspects of the mRNA that affect the final expression of a gene. mRNA abundance of a number of well-known AD-relevant genes are regulated by RBPs or microRNAs bound to their 3’ UTRs. Genetic variants that affect these regulatory mechanisms will lead to abnormal mRNA expression, thus significantly altering related functional pathways. In this project, we will leverage the large collection of public data sets on RBP-RNA interaction profiling, RNA-seq and genotyping data collected from AD and control subjects, and our in-house data generation. We will develop and apply novel methodologies to make full use of these data sets, complemented by further bioinformatic prediction and high-throughput experimental testing, to pinpoint 3’ UTR genetic variants that alter mRNA abundance in AD. This work will allow a previously unattained level of understanding of genetic variants in post-transcriptional regulation and provide new means to tackle the imperative task of functional interpretation of genetic variants in AD.