# Deciphering the genetic mechanisms of atrial fibrillation

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $655,247

## Abstract

Atrial fibrillation (AF) is an important and increasing public health problem. Most cases occur in the elderly and
so the incidence of the problem is rising; the number of Americans affected with AF is expected to surge to ~16
million by 2050. Other clinical features include hypertension and underlying heart disease while many relatively
young patients have no apparent risk factors and are designated as “lone” or early-onset AF (EOAF). The AF
epidemic is further complicated by the lack of effective therapies. The limited success of treatments stems in
part from an incomplete understanding of the pathophysiology of AF and failure to target therapy to the
underlying mechanisms. Traditionally, AF was considered to be a sporadic, non-genetic disorder but we and
others have shown that EOAF has a substantial genetic basis. Positional cloning and candidate gene
approaches have linked mutations in cardiac ion channels, and signaling molecules with EOAF. While these
studies have provided important insights into underlying mechanisms, most of the rare variation in
susceptibility to EOAF remains unknown. Given recent advances in next generation sequencing (NGS),
discovery of novel genes in other cardiovascular phenotypes and our preliminary data, the overarching goal
of this proposal is to use NGS to identify novel AF genes and decipher the underlying genetic mechanisms of
EOAF. Our clinical-DNA registries have systematically enrolled over 60 families from diverse ethnic
background with early-onset familial AF. We propose to use this large and well-characterized cohort to address
two specific aims: Aim 1 will conduct a multi-tiered stepwise approach to identify rare genetic variants linked
with EOAF. First whole exome sequencing (WES) will be performed in our existing 60 EOAF families, who do
not harbor candidate gene variants, to identify rare variants predicated on rarity, ethnicity, co-segregation with
AF, predicted pathogenicity and bioinformatics filtering. Second, the most promising variants will replicated in
AFGen Consortium TOPMed Cohort in which over 3,500 probands with EOAF and 3,500 controls have
undergone whole genome sequencing (WGS). This aim builds on our published study in which we identified
five novel candidate AF genes using a WES approach and the recent successful completion of WGS in EOAF
probands in the TOPMed Cohort. Aim 2 will determine the underlying genetic mechanisms of EOAF by
functionally characterizing high priority rare variants using in vitro electrophysiology and in vivo functional
assays in zebrafish to enable disease-association. This aim builds upon our prior work where we have
functionally characterized a rare AF-linked variant in the Ca channel gene identified by WES and identified rare
developmental genes that modulate cardiac conduction in zebrafish. These studies will not only identify novel
AF genes and provide insights into underlying genetic mechanisms of EOAF but will also uncover novel
therapeutic approaches fo...

## Key facts

- **NIH application ID:** 9981002
- **Project number:** 5R01HL138737-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Dawood Darbar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $655,247
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981002

## Citation

> US National Institutes of Health, RePORTER application 9981002, Deciphering the genetic mechanisms of atrial fibrillation (5R01HL138737-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9981002. Licensed CC0.

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