# High-resolution Genetic Mapping of Maternal Effects and Epistatic Suppressors of Congenital Heart Disease Risk

> **NIH NIH F30** · WASHINGTON UNIVERSITY · 2020 · $2,975

## Abstract

PROJECT SUMMARY / ABSTRACT
 Congenital heart disease (CHD) is the most common congenital anomaly, which leads to significant
morbidity and mortality in newborns. Although great surgical advances have reduced CHD mortality in newborns
and children, these patients are not cured. Many of these children grow up and experience serious morbidity and
truncated lifespans as adults. It has become evident that we need strategies to move our efforts away from
intervention and toward prevention. The first step in this endeavor is to understand the causes of CHD.
Surprisingly, environment and mutations are estimated to explain less than one-third of CHD cases. In many
cases, however, even when a vital cardiac gene is mutated, a heart defect does not occur. This highlights the
critical role that genetic modifiers have in CHD pathogenesis. Attempts to identify these modifier genes have had
marginal success in humans. This motivated us to look toward animal models, in which we can control the effects
of environment and genetics.
 Our mouse model replicates CHD risk in susceptible people through a heterozygous mutation in Nkx2-5,
an essential cardiac transcription factor. We then use inbred strain crosses and quantitative genetic methods to
identify genetic polymorphisms that modify CHD risk in Nkx2-5+/- mice. Through this model system, we
inadvertently confirmed observations in humans that the offspring of older mothers have an elevated risk for CHD
even after ruling out aneuploidy. We also determined that this risk is due to factors within old mothers, not old
eggs. Remarkably, voluntary exercise for the aging mother is sufficient to reduce CHD risk to baseline levels.
Subsequent studies demonstrated that the magnitude of the maternal aging risk varied according to the genetic
background of our mice. This indicates that the age risk is a quantitative trait that regulates maternal factors,
which can either inflate or suppress the risk of CHD. In separate experiments focused on risk modifiers within
susceptible individuals, I discovered genetic loci that act as epistatic suppressors of CHD risk in multiple mouse
populations. If we were able to identify the genes responsible and mimic the effects of maternal exercise or
protective genetic loci, we could translate these benefits to the general population. Our past experiments were not
designed to detect individual genes. So instead of speculating about the genes responsible for the maternal age-
associated risk and epistatic suppression of CHD, we have chosen a prudent and unbiased approach to identify
these genes. We have partnered with the laboratory of James Cheverud to use a high-resolution, advanced
intercross mapping population to identify CHD modifier loci to nearly single-gene resolution. This study will be
the first to map novel genes and variants that modify CHD risk at high-resolution, and these results will serve as
a springboard for future research into congenital heart disease prevention.
We propose t...

## Key facts

- **NIH application ID:** 9859438
- **Project number:** 5F30HL136077-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Ehiole Ogboma Akhirome
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,975
- **Award type:** 5
- **Project period:** 2017-02-01 → 2020-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859438

## Citation

> US National Institutes of Health, RePORTER application 9859438, High-resolution Genetic Mapping of Maternal Effects and Epistatic Suppressors of Congenital Heart Disease Risk (5F30HL136077-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859438. Licensed CC0.

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