# Epigenome-Guided Causal Variant Discovery and Mechanisms

> **NIH NIH R01** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2021 · $641,098

## Abstract

PROJECT SUMMARY
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by dysregulated
interferon responses and loss of self-tolerance to cellular antigens, which result in inflammatory processes that
ultimately lead to systemic end-organ damage. Despite decades of research, the underlying mechanisms
driving the pathogenesis of SLE remain incompletely understood. Genome-wide association studies (GWAS)
have identified over 100 SLE risk haplotypes carrying hundreds of SNPs with unknown functional importance
in disease onset and progression. Distinguishing causal from non-causal SNPs, and thus translating genetic
knowledge into actionable clinical knowledge has been a laborious, inefficient, and resource-intensive task.
Our laboratory has developed a new approach to expedite the causal variant discovery process where we use
the epigenome to identify likely causal variants on risk haplotypes. We do this by identifying epigenetic
footprints of allelic imbalance at SNPs (“hQTLs”) in poised and active enhancers measured by ChIP-
sequencing. Our approach is able to identify causal variants in the context of linkage disequilibrium and
provides a priori evidence that the putative causal variant is functional by identifying allelic imbalance in the
magnitude of histone marks. We also use 3D chromatin topology data to construct a molecular wiring diagram
of interacting enhancers and promoters that contain hQTLs. Since these data leverage the epigenome distinct
profiles in specific cells and cell states provide important contextual information about what cellular processes
the epiQTL is most important in regulating. This resubmission of R01 AR073606 aims to 1) use an
epigenome-guided approach to identify resting and stimulus-dependent hQTLs from primary B cells; 2) validate
and confirm the allele-specific transcriptional regulation attributed to hQTLs using an orthogonal massively
parallel reporter assay; and 3) determine how hQTLs modify gene expression and 3D chromatin organization
of genes contained within regulatory networks of hQTLs using multiplex quantitative PCR and chromatin
conformation capture (3C). We believe this project positions us at the leading edge of causal variant
identification and risk haplotype functional characterization and will contribute to a better understanding of the
connection between genotype and phenotype for human SLE and related autoimmune diseases.

## Key facts

- **NIH application ID:** 10158442
- **Project number:** 5R01AR073606-03
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Patrick M Gaffney
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $641,098
- **Award type:** 5
- **Project period:** 2019-05-06 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158442

## Citation

> US National Institutes of Health, RePORTER application 10158442, Epigenome-Guided Causal Variant Discovery and Mechanisms (5R01AR073606-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10158442. Licensed CC0.

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