# A Twin Approach for Genome-Wide Differential DNA Methylation in Orofacial Clefting

> **NIH NIH K01** · UNIVERSITY OF IOWA · 2020 · $139,234

## Abstract

Abstract
Nonsyndromic orofacial clefts (OFCs) are the most common craniofacial birth defects in humans, affecting
approximately 1 in 700 individuals worldwide. Genome-wide linkage and association studies have identified
several risk alleles for OFCs; however, they account for a minority of their estimated heritability. Therefore,
while the ongoing genetic and expression studies may lead to important advances in understanding the
biological basis underlying OFCs, a fuller picture will only emerge as the interaction of susceptibility variants
with other factors, such as epigenetic changes, are established. Epigenetic modification is a likely mechanism
through which environmental factors and genetic variation may alter gene expression. DNAm is a covalent
addition of a methyl (CH3) group to the nucleotide cytosine, which can lead to changes in transcriptional
activity of the targeted gene. We hypothesize that changes in methylation and the resulting differential gene
expression is an epigenetic risk factor for OFCs, and that DNAm mediates genetic influences in OFCs risk. Our
main goals are to characterize genome-wide DNAm variation that can impact the risk for OFCs; and explore
the genetic-epigenetic interactions (meQTLs) involved in the etiology of OFC. To do so, this project proposes a
powerful strategy using the largest sample set (to date) of monozygotic twins and sibling pairs discordant for
nonsyndromic OFCs used to study epigenetic risk factors. This is a key step and an innovative approach that
will allow uncovering epigenetics risk factors that are invisible to conventional GWAS and DNA sequencing
methods. The central hypothesis of this proposal will be tested with the following specific aims: (1) To
determine genome-wide DNA methylation patterns in MZ twins discordant for OFCs; (2) To explore the
genetic-epigenetic interactions (meQTLs) involved in the etiology of OFCs. Within aim 2 we will attempt
to replicate the genetic-epigenetic interactions identified in the preliminary analysis (obtained since the first
submission of this proposal), and top hits resulting from Aim 1, using an independent cohort of cleft discordant
sibling pairs. The outstanding team of mentors (Dr. Jeff Murray, Dr. Robert Philibert, Dr. Mary Marazita, and
Dr. Moreno-Uribe), consultants (Dr. Xie, and Dr. Drake), collaborator (Dr. Lie), and advisors (Dr. Amendt, Dr.
Wehby and Dr. Butali) assembled in this proposal covers all areas of the much needed additional training
necessary to accomplish the proposed research and training aims. They will provide guidance and facilitate the
growth of the PI during the transition to independence. Although very well trained initially, the five years hiatus
in the PI's career justify the need for additional training in the rapidly moving fields of epigenetics and big data
applications. The proposed training and research aims are tailored to build upon the PI's previous experience
and to provide the additional training in epigenetics a...

## Key facts

- **NIH application ID:** 9980356
- **Project number:** 5K01DE027995-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Aline L Petrin
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $139,234
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980356

## Citation

> US National Institutes of Health, RePORTER application 9980356, A Twin Approach for Genome-Wide Differential DNA Methylation in Orofacial Clefting (5K01DE027995-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980356. Licensed CC0.

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