GWAS Analysis Reveals Previously Unknown Genomic Variants Associated with Different Subgroups of Congenital Heart Disease

Objectives: Congenital heart disease (CHD) covers a wide spectrum of cardiac defects ranging from simple persistent foramen ovale (PFO) to severe malformations such as the hypoplastic left heart syndrome (HLHS). The genetic cause remains largely unknown. Therefore, we performed a genome-wide association study (GWAS) to identify genetic variants associated with CHD.

Methods: A total of 1,827 patients and 3,753 healthy controls were included in the study. The cohort of CHD patients comprises a representative distribution of all major CHD subgroups. Genomic DNA was purified from blood samples. GWAS analysis was performed using an Affymetrix Genome-wide human SNP array. After quality check 1,506 cases and 3,554 controls and 429,808 variants were finally analyzed.

Results: After imputation we first analyzed the whole population for the presence of significant variants. Indeed, one SNP located on chromosome 12 was identified which showed genome-wide significance (p < 10⁻⁸). We then examined the five largest subgroups in our CHD patient cohort (septal defects, right and left heart lesions, transposition of the great arteries, thoracic artery and vein anomalies). No conspicuous variants were identified in the group with transposition of the great arteries (n = 146). Three SNPs located on chromosomes 10, 13 and 16 (all with a significance of p < 10⁻⁶) were associated with septal defects (n = 445). In right (n = 270) and left heart (n = 138) lesions two variants on chromosomes 7 and 8, respectively, showed a strikingly elevated frequency (p < 10⁻⁶ and p < 10⁻⁷). Two loci on chromosomes 3 and 13, respectively, with a significance of p < 10⁻⁶ were identified in the group of thoracic artery and vein anomalies (n = 205). Finally, we have analyzed the subgroup with conotruncal heart defects (n = 350). Within this subgroup two loci were identified: the first on chromosome 13 with a significance of p < 10⁻⁶ while the second locus on chromosome 12 almost reached genome-wide significance.

Conclusion: GWAS identified several, previously unknown genomic variants which are associated with different subgroups of CHD. Our results add a further piece of knowledge to the better understanding of the underlying genetics in CHD.