The impact of nationwide folic acid fortification on genetic variants associated with conotruncal heart defects.
7 affiliations
- 1Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States. [email protected].
- 2Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States. [email protected].
- 3Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States.
- 4Department of Epidemiology, UTHealth Houston School of Public Health, Houston, TX, United States.
- 5Division of Medical Genetics, Department of Pediatrics, McGovern Medical School at UTHealth Houston, Houston, TX, United States.
- 6Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States.
- 7Division of Neonatal-Perinatal Medicine, Department of Pediatrics, McGovern Medical School at UTHealth Houston, Houston, TX, United States. [email protected].
Abstract
Folate deficiency is associated with increased risk of conotruncal heart defects (CTHD), but its interaction with genetic factors remains unclear. Our objective was to investigate genome-wide associations between common genetic variants and birth before versus after universal folic acid fortification among children with CTHD and other heart defects. Sequencing data were available through the Pediatric Cardiac Genomics Consortium, aligned to the human reference genome (GRCh38/hg38), and jointly processed to ensure uniform variant detection and minimize batch effects. Analyses were restricted to individuals with European-inferred genetic ancestry, limiting generalizability to other ancestral groups. Genome-wide association study (GWAS) models compared allele frequencies across fortification eras among all participants (n = 1285), the subset with CTHD (n = 534), and the remaining individuals with other heart defects (n = 751). Functional enrichment was assessed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Among the full analytic group, eight loci had at least two suggestive variants before compared to after fortification. Among the subset with CTHD, two variants located in DHRS3 (rs7551703, odds ratio [OR] 2.10, and rs6541043, OR 2.21) and four variants located in PPARGC1B showed suggestive association after fortification (OR 4.47-4.51). Enriched biological pathway terms were consistent with cardiac developmental processes. In summary, this study examined the association between folic acid fortification and genetic risk for CTHD and other heart defects and identified associations with fortification era that suggest some shift in risk following fortification. Identified pathways suggest gene-nutrient interactions may modulate cardiac developmental pathways, underscoring the relationship between maternal folate status and cardiovascular development.
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BibTeX
@article{morton2026impact,
title = {{The impact of nationwide folic acid fortification on genetic variants associated with conotruncal heart defects.}},
author = {Sarah U Morton and Enrique Mondragon-Estrada and Rui Qian and Omobola O Oluwafemi and Kit Sing Au and Hope Northrup and Wendy K Chung and A J Agopian and Tina O Findley},
journal = {Human genetics},
year = {2026},
month = oct,
doi = {10.1007/s00439-026-02888-5},
url = {https://europepmc.org/article/MED/42911416},
note = {CC BY},
}
RIS
TY - JOUR
TI - The impact of nationwide folic acid fortification on genetic variants associated with conotruncal heart defects.
AU - Sarah U Morton
AU - Enrique Mondragon-Estrada
AU - Rui Qian
AU - Omobola O Oluwafemi
AU - Kit Sing Au
AU - Hope Northrup
AU - Wendy K Chung
AU - A J Agopian
AU - Tina O Findley
PY - 2026
DA - 2026/10/22
JO - Human genetics
DO - 10.1007/s00439-026-02888-5
UR - https://europepmc.org/article/MED/42911416
AB - Folate deficiency is associated with increased risk of conotruncal heart defects (CTHD), but its interaction with genetic factors remains unclear. Our objective was to investigate genome-wide associations between common genetic variants and birth before versus after universal folic acid fortification among children with CTHD and other heart defects. Sequencing data were available through the Pediatric Cardiac Genomics Consortium, aligned to the human reference genome (GRCh38/hg38), and jointly processed to ensure uniform variant detection and minimize batch effects. Analyses were restricted to individuals with European-inferred genetic ancestry, limiting generalizability to other ancestral groups. Genome-wide association study (GWAS) models compared allele frequencies across fortification eras among all participants (n = 1285), the subset with CTHD (n = 534), and the remaining individuals with other heart defects (n = 751). Functional enrichment was assessed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Among the full analytic group, eight loci had at least two suggestive variants before compared to after fortification. Among the subset with CTHD, two variants located in DHRS3 (rs7551703, odds ratio [OR] 2.10, and rs6541043, OR 2.21) and four variants located in PPARGC1B showed suggestive association after fortification (OR 4.47-4.51). Enriched biological pathway terms were consistent with cardiac developmental processes. In summary, this study examined the association between folic acid fortification and genetic risk for CTHD and other heart defects and identified associations with fortification era that suggest some shift in risk following fortification. Identified pathways suggest gene-nutrient interactions may modulate cardiac developmental pathways, underscoring the relationship between maternal folate status and cardiovascular development.
SN - 0340-6717
SN - 1432-1203
ER -