# High throughput functional studies of IBD-associated GWAS variants

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $637,105

## Abstract

PROJECT SUMMARY/ABSTRACT
The Inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are chronic
inflammatory diseases of the gastrointestinal tract with no cure. Genome-wide association studies (GWAS) have
found >250 genomic loci associated with IBD, but variant contributions to mechanisms driving IBD pathogenesis
and disease prognosis remain unclear. Each locus typically contains tens to hundreds of variants, the vast
majority of which are in non-coding regions suggesting a role in gene regulation. For most loci, the causal variant,
the affected regulatory element, and the target gene being regulated are unknown. We hypothesize that
regulatory variants contribute to IBD phenotypes by altering gene transcriptional programs driving phenotypic
heterogeneity. We propose to identify putative casual regulatory variants using two, orthogonal, high-throughput
analyses. Aim 1: Regulatory quantitative trait loci (QTL) for chromatin accessibility (caQTL) and transcription
factor binding (tfQTL) associate genetic variation with alterations in regulatory activity. For variants in GWAS
loci, these analyses will identify regulatory variants with potential contributions to regulation in disease-relevant
cell types and tissues. Aim 2: Alternatively, massively parallel reporter assays (MPRA) systematically interrogate
allelic effects on transcriptional regulation of thousands of genetic variants. MPRA using vectors of human DNA
regulatory elements containing IBD associated variants of interest can be performed in mouse cells or organs
due to the well-established conservation of transcription factor motifs between human and mouse. We will use
MPRA to determine variants that alter regulatory activity in colon, ileum, and mesenteric lymph nodes under both
normal and LPS-stimulated inflammatory states. Aim 3: Integrating results from QTL and MPRA assays, we will
select high confidence putative IBD regulatory variants for intestinal epithelial cell focused functional validation
in patient derived 2D intestinal monolayer systems. The long-term goals of this project are: 1) To fill the gap
between our ability to detect genetic, gene regulatory, and gene expression variation linked to IBD and our ability
to explain how that variation ultimately contributes to IBD; and 2) To provide a unique data resource for IBD
investigators to access for their own studies.

## Key facts

- **NIH application ID:** 10814931
- **Project number:** 5R01DK136262-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Terrence S. Furey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $637,105
- **Award type:** 5
- **Project period:** 2023-04-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814931

## Citation

> US National Institutes of Health, RePORTER application 10814931, High throughput functional studies of IBD-associated GWAS variants (5R01DK136262-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10814931. Licensed CC0.

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