# Discovery and interrogation of genetic regulatory variation impacting Atrial Fibrillation risk

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2023 · $803,105

## Abstract

Abstract
 The overall goal of this multi-principal investigator proposal is to facilitate the transition from implication
of genetic variants identified in extensive genome wide association studies (GWAS) of Atrial Fibrillation (AF) to
the molecular mechanisms underlying AF risk. We hypothesize that a novel genomic and analytic pipeline
interrogating regulatory function of genetic variation will identify candidate causative variants and their target
genes, enabling the transition from simple associations to causative mechanisms for the arrhythmia. In
preliminary studies, we have applied novel single cell approaches to generate cell-type-resolved high-resolution
chromosome accessibility maps and taken advantage of coordinated genomic signals to link AF risk variants to
candidate causative AF genes. The results describe a highly interconnected gene regulatory network for cardiac
atrial gene expression. In our first aim we propose to generate multi-modal single-cell genomics data to provide
higher-resolution annotation of variant effects. We will improve our computational procedure to better leverage
these datasets for AF variant and gene discovery. In our second aim, we will interrogate the interconnected
gene regulatory network in molecular enhancer assays and genomic chromatin conformation capture
experiments, to directly examine the impact of nominated genetic variants and their physical association with
candidate target genes. In our third aim, we will examine the functionality of high confidence variant SNPs in
depth, including their impact on gene regulation in cis, their impact on human cardiomyocyte electrophysiology,
and their impact on cardiomyocyte gene expression and chromatin status in trans. We have established a
tractable strategy that will help enable the transition from AF risk variants to molecular mechanisms. We
anticipate that our approach will help translate the promise of AF genetics into meaningful biological insights for
AF and establish a paradigm for the molecular understanding of genetic association studies in any system.

## Key facts

- **NIH application ID:** 10593080
- **Project number:** 5R01HL163523-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Xin He
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $803,105
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10593080

## Citation

> US National Institutes of Health, RePORTER application 10593080, Discovery and interrogation of genetic regulatory variation impacting Atrial Fibrillation risk (5R01HL163523-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10593080. Licensed CC0.

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