Genetic Variants Associated With Congenital Heart Disease: A Meta-Analysis of Ethnicity and Subtype-Specific Susceptibility

Congenital heart disease (CHD) is the most common heterogeneous birth defect, with prevalence varying across populations. A comprehensive meta-analysis could refine the genetic risk estimates and enhance our understanding of CHD susceptibility. We conducted a meta-analysis of 175 case-control studies investigating 107 genetic variants across 72 gene regions. Pooled odds ratios were calculated using 6 genetic models, with subgroup analyses by ethnicity and CHD subtype. Gene Ontology and network analyses elucidated the functional significance of implicated genes. Thirty-six variants were significantly associated with CHD (P<0.05), including 7 missense mutations in NRP1, MTHFR, MTRR, NOS3, and DNMT1. Ten variants, including rs1531070 in MAML3 (odds ratio, 1.52; P=5.9×10-15), surpassed genome-wide significance. Ethnicity-specific analyses identified 13 significant variants, including MTHFR-rs1801131 in Chinese (P=1.71×10-10), STX18-AS1-rs870142 in Europeans (P=7.13×10-16), and MTRR-rs1801394 in Middle Eastern populations (P=9.8×10-8). Subtype analyses revealed 25 variants associated with specific CHD subtypes, such as STX18-AS1-rs16835979 with atrial septal defect (P=2.1×10-16) and variants in MTHFR, NRP1, and PTPN11 with tetralogy of Fallot (P=3.0×10-17-2.33×10-10). The rs1801133 variant was linked to double-outlet right ventricle (P=3.0×10-11) and patent ductus arteriosus (P=6.5×10-9). Gene Ontology and network analyses highlighted genes involved in cardiac development and folate metabolism in CHD pathogenesis. This meta-analysis refines CHD risk estimates across diverse ancestries and subtypes, underscoring the complex genetic architecture of the disease. Variants involved in cardiac development and metabolic pathways represent promising targets for precision medicine in CHD.