The impact of nationwide folic acid fortification on genetic variants associated with conotruncal heart defects

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.