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, with pathways suggesting gene-nutrient interactions may modulate cardiac developmental pathways.
Key Findings
Methods
Genome-wide association analyses compared allele frequencies in children born before versus after universal folic acid fortification among European-ancestry individuals with congenital heart defects.
Sequencing data came from the Pediatric Cardiac Genomics Consortium, aligned to GRCh38/hg38 and jointly processed to ensure uniform variant detection and minimize batch effects.
The full analytic group included n = 1285 participants; the subset with conotruncal heart defects (CTHD) was n = 534; the remaining individuals with other heart defects numbered n = 751.
Analyses were restricted to individuals with European-inferred genetic ancestry, which limits generalizability to other ancestral groups.
Results
In the full analytic group, eight loci had at least two suggestive variants associated with birth before compared to after fortification.
The comparison was of allele frequencies across fortification eras among all 1285 participants.
The abstract does not report genes or effect sizes for these eight loci.
Results
Among children with CTHD, two variants in DHRS3 showed suggestive association with birth after fortification.
rs7551703 had an odds ratio (OR) of 2.10.
rs6541043 had an OR of 2.21.
The subset with CTHD included n = 534.
Results
Among children with CTHD, four variants in PPARGC1B showed suggestive association with birth after fortification, with larger effect sizes than the DHRS3 variants.
ORs ranged from 4.47 to 4.51.
Associations were described as 'suggestive', not as genome-wide significant.
Results
Functional enrichment analysis using DAVID yielded biological pathway terms consistent with cardiac developmental processes.
Enrichment was assessed using the Database for Annotation, Visualization and Integrated Discovery (DAVID).
The authors interpret the pathways as suggesting that gene-nutrient interactions may modulate cardiac developmental pathways.
Conclusions
The authors conclude that associations with fortification era suggest some shift in genetic risk for CTHD and other heart defects following fortification.
The findings are interpreted as underscoring the relationship between maternal folate status and cardiovascular development.
Generalizability is limited by restriction to European-inferred ancestry.
What This Means
Since the late 1990s, folic acid has been added to grain products in the United States to help prevent birth defects. Low folate levels in mothers have been linked to a higher chance of heart defects in babies, including conotruncal heart defects, which affect the heart's major outflow vessels. This study asked whether the genetic variants seen in children with heart defects differ between those born before and those born after fortification began.
Researchers analyzed genetic sequencing data from 1,285 children of European ancestry with heart defects, including 534 with conotruncal defects. They found several genetic regions where variant frequencies differed between the before and after eras. In children with conotruncal defects, variants in two genes, DHRS3 and PPARGC1B, were more common among those born after fortification. The associations were only suggestive, not definitive. The genes involved were linked to pathways of heart development.
This research suggests that folic acid fortification may be associated with a shift in which genetic risk factors are seen in children with heart defects, pointing to possible interactions between genes and nutrition. The findings are preliminary and cannot show cause and effect. They apply only to people of European ancestry, and further studies in larger and more diverse groups would be needed to confirm them.
Morton S, Mondragon-Estrada E, Qian R, Oluwafemi O, Au K, Northrup H, et al.. (2026). The impact of nationwide folic acid fortification on genetic variants associated with conotruncal heart defects.. Human genetics. https://doi.org/10.1007/s00439-026-02888-5