Edsel Abud, United States of America

University of California Irvine Department of Neurobiology & Behavior

Author Of 1 Presentation

INTEGRATION OF ALZHEIMER'S DISEASE GENETICS, MYELOID CELL GENOMICS AND GENE REGULATORY NETWORKS REVEALS NOVEL DISEASE RISK MECHANISMS

Session Type
SYMPOSIUM
Date
14.03.2021, Sunday
Session Time
12:00 - 14:00
Room
On Demand Symposia C
Lecture Time
12:00 - 12:15
Session Icon
On-Demand

Abstract

Aims

We aim to identify myeloid regulatory elements that are enriched in Alzheimer’s disease (AD) risk alleles, identify their target genes and nominate candidate causal variants in disease risk loci. We also want to study the likely downstream effects of AD risk genes and functionally validate these findings in microglia.

Methods

Integration of myeloid epigenomic, chromatin interactions and quantitative trait loci (QTL) datasets as well as a Mendelian Randomization framework were used to link AD enhancers to their target genes. Fine-mapping analyses were used to nominate candidate causal variants and generate the mechanism of action hypotheses. Gene regulatory networks were used to study the regulons of AD risk genes. Knockdown and overexpression studies were utilized to validate these findings.

Results

We found that myeloid active enhancers are enriched in AD risk alleles. We linked these enhancers to their likely target genes, nominating AD risk genes in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants in these loci. In the MS4A locus we identified a candidate functional variant and validated it in microglia and the brain. We highlight the coalescence of candidate causal genes in the myeloid endolysosomal system. We constructed myeloid single-cell gene regulatory networks and found that the predicted targets of SPI1, an AD risk gene, were enriched in the endolysosomal compartment. We validate these findings in Spi1 knockdown and overexpression experiments in microglia.

Conclusions

This study explores the links between AD risk variants, myeloid enhancer activity, gene expression and subsequent network-level dysregulations that likely contribute to AD risk modification.

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