FunGen-xQTL: Unraveling the genetic basis of molecular functions in Alzheimer's Disease

Project Summary In this project, we propose to identify causal genes, cell types, and molecular mechanisms in Alzheimer’s disease (AD) by leveraging genetics as natural perturbation experiments across multi-omics data — a unique approach to establish causality in human brain samples where experimental manipulation is not possible. Building upon the successful pilot phase of the ADSP Functional Genomics Consortium xQTL Project (FunGen-xQTL), we integrate multi-ancestry molecular quantitative trait loci (xQTL) across brain cells, cerebrospinal fluid (CSF), and blood to address key challenges in AD genetics: determining causal relationships between brain and blood regulation, identifying disease-relevant cell contexts, and bridging the gap between GWAS findings and molecular mechanisms. Our approach combines deep molecular profiling of understudied brain cell populations with advanced computational methods across four specific aims: (1) Generating and fine-mapping molecular QTL in rare brain cell types across ancestries, with unprecedented profiling of 450 African Americans and 350 Hispanic individuals; (2) Integrating xQTL data from brain, CSF, and blood to uncover coordinated neurovascular regulation and causal relationships between tissues in AD; (3) Developing advanced computational methods including AI-powered prediction and causal multi-context analysis to identify disease-causing genes and their relevant cellular contexts; and (4) Investigating molecular mechanisms of prioritized targets through systematic functional studies using human iPSCs. The impact extends beyond creating a comprehensive multi-ancestry xQTL resource – our systematic approach to disentangle complex regulatory mechanisms will establish precise cellular and molecular targets for therapeutic development in AD and related dementias.