# AD GxE: In vivo and in vitro modeling of gene x environment interactions

> **NIH NIH U01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $763,225

## Abstract

Project Summary
Common genetic variants identified through genome-wide association studies have been reproducibly
associated with risk for Alzheimer’s disease (AD), but the function of many risk variants are unknown and likely
context-specific. At the same time, several environmental exposures have been implicated in AD and dementia,
including particulate matter air pollution (PM2.5), heavy metals (especially lead (Pb)), and infections. We posit
that the genetic architecture of AD includes gene-environment interactions (GxE) between common, non-coding
variants and environmental exposure. Here, we propose to identify these GxE using an in vitro model, "GxE in
a dish", using the inherent genetic diversity in a population of neural cells exposed to AD-relevant environmental
exposures. We will test the context-specific function of common genetic variation in 100 induced pluripotent stem
cell donors differentiated to cortical organoids. We will expose the organoids to PM2.5, Pb, infection mimics (LPS
+ IFNγ), or vehicle. We will collect scRNA-seq data from each exposed organoid, allowing inference of context-
specific single cell expression quantitative trait loci (QTL). To find genetic variants associated with neural cell
survival, we will additionally generate chimeric brain organoids composed of cells derived from multiple
independent donors. We will use the Census-seq approach to determine the proportion of each donor within the
chimeric organoids in response to the exposures described above. We will then conduct a genetic association
study to find common variants associated with differential survival response to these environmental exposures.
To complement our in vitro cell culture model, we will also identify GxE effects on brain structure in vivo using a
large population scale database. We will then colocalize context-specific eQTLs, survival QTLs, and in vivo brain
QTLs with each other and AD GWAS loci. In all, our results will reveal new mechanisms underlying AD GWAS
loci by exploring the context-specific nature of genetic variant function using both in vitro and in vivo systems.

## Key facts

- **NIH application ID:** 10973807
- **Project number:** 1U01AG088667-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jason Louis Stein
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $763,225
- **Award type:** 1
- **Project period:** 2024-09-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10973807

## Citation

> US National Institutes of Health, RePORTER application 10973807, AD GxE: In vivo and in vitro modeling of gene x environment interactions (1U01AG088667-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10973807. Licensed CC0.

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