# Aberrant DNA Methylation Underlying Prenatal Exposures and Increased Newborn and Childhood Adiposity

> **NIH NIH R01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2023 · $338,027

## Abstract

Project Summary
The origins of childhood obesity and subsequent poor metabolic health may begin in utero. The
Hyperglycemia and Adverse Pregnancy Outcome Follow Up Study (HAPO FUS) provides substantial
evidence that maternal hyperglycemia and BMI during pregnancy are strongly associated with obesity in
their 10-14 year old children. However, a knowledge gap exists as mechanisms mediating the pathway
between an adverse uterine environment and childhood obesity development have not been elucidated.
Epigenetic DNA alterations triggered by an adverse uterine environment is a possible mechanism
underlying associations between maternal hyperglycemia/obesity and childhood obesity. We hypothesize
that aberrant offspring DNA methylation occurs in response to an adverse intrauterine environment,
characterized by maternal hyperglycemia and/or obesity. Differential DNA methylation (DNAm) may
affect metabolically-important genes contributing to fetal programming of adiposity, and higher rates of
childhood obesity. To investigate these important questions, we will take advantage of the HAPO FUS
cohort on whom we have detailed information about the uterine environment, direct measurements of
newborn and childhood adiposity, and existing genetic data. Using stored cord blood and childhood DNA of
3243 HAPO FUS participants, the goals of this project are to conduct DNA methylation studies utilizing the
MethylationEPIC 850K BeadChip (Illumina Infinium). In Aim 1, we will investigate cord blood DNAm in
select candidate genes proposed to play a critical role linking maternal hyperglycemia/ BMI to newborn and
childhood adiposity outcomes in HAPO FUS. Potential methylation-related mechanisms underlying these
associations will be identified using mediation analysis. In Aim 2, we will integrate cord blood DNAm profile
and existing SNP data from the HAPO genome-wide association study with mapping of methylation
quantitative trait loci (mQTL) in order to elucidate the genetic architecture of CpG sites associated with
offspring adiposity traits. We will then perform 2-step Mendelian randomization to identify causal CpG loci.
In Aim 3, we will conduct epigenome-wide association studies on cord blood DNA to enable discovery of
new genes linking an adverse maternal milieu with offspring adiposity. Replication of significant DNAm
findings from HAPO FUS will be conducted in the Gen3G cohort to ensure reproducibility and rigor of this
proposal. Methylation in specific genes may serve as biomarkers when evaluating if interventions are
effictive. Discovery of novel biomarkers will enable primordial prevention strategies to curtail the vicious
cycle of transgenerational obesity.

## Key facts

- **NIH application ID:** 10543751
- **Project number:** 5R01DK118403-05
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Jami L Josefson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $338,027
- **Award type:** 5
- **Project period:** 2019-01-10 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10543751

## Citation

> US National Institutes of Health, RePORTER application 10543751, Aberrant DNA Methylation Underlying Prenatal Exposures and Increased Newborn and Childhood Adiposity (5R01DK118403-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10543751. Licensed CC0.

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