Genetic Mapping of m6A and Pseudouridine RNA Modifications in the Aging Human Brain and Their Impact on Alzheimer's Disease

PROJECT SUMMARY In this project, we propose to investigate the role of RNA modifications in Alzheimer's disease (AD) through an innovative integration of genetics, multi-omics analysis, and functional validation. Recognizing that the molecular mechanisms underlying AD onset and progression remain incompletely understood, our study aims to examine how genetic variants influence N6-methyladenosine (m6A) and pseudouridine (Ψ) modifications in aging brains and their contributions to AD pathogenesis. Our overarching goal is to map RNA modifications in human brain cells, identify their genetic regulators, and understand their causal roles in AD through three integrated aims: (1) Creating a comprehensive atlas of m6A and Ψ modifications in human brain cells from multiple ancestries and mapping their quantitative trait loci (RNAmQTL); (2) Integrating RNAmQTL with other molecular QTL and AD genome-wide association study (GWAS) data to elucidate the molecular functions of RNA modifications and their impact on AD; and (3) Characterizing molecular and cellular phenotypes of candidate m6A sites and AD risk genes using human iPSC models. The impact of this work extends beyond providing the first genetic study of RNA modifications in human brain. By leveraging genetic variation as natural perturbations, we can distinguish causal factors in AD pathogenesis from reactive changes that merely respond to disease progression. Our approach combines novel experimental technologies (CAM-seq, BID-seq) with advanced statistical methods for multi-context QTL integration (ColocBoost, multi-cTWAS) to reveal new mechanisms underlying AD. This project promises to identify novel therapeutic targets with clear genetic underpinnings, potentially leading to the discovery of new AD biomarkers and treatment strategies.