Genome-Wide Association Studies and Meta-Analyses for Congenital Heart Defects

Circ Cardiovasc Genet. 2017 Jun;10(3):e001449. doi: 10.1161/CIRCGENETICS.116.001449.


Background: Maternal and inherited (ie, case) genetic factors likely contribute to the pathogenesis of congenital heart defects, but it is unclear whether individual common variants confer a large risk.

Methods and results: To evaluate the relationship between individual common maternal/inherited genotypes and risk for heart defects, we conducted genome-wide association studies in 5 cohorts. Three cohorts were recruited at the Children's Hospital of Philadelphia: 670 conotruncal heart defect (CTD) case-parent trios, 317 left ventricular obstructive tract defect (LVOTD) case-parent trios, and 406 CTD cases (n=406) and 2976 pediatric controls. Two cohorts were recruited through the Pediatric Cardiac Genomics Consortium: 355 CTD trios and 192 LVOTD trios. We also conducted meta-analyses using the genome-wide association study results from the CTD cohorts, the LVOTD cohorts, and from the combined CTD and LVOTD cohorts. In the individual genome-wide association studies, several genome-wide significant associations (P≤5×10-8) were observed. In our meta-analyses, 1 genome-wide significant association was detected: the case genotype for rs72820264, an intragenetic single-nucleotide polymorphism associated with LVOTDs (P=2.1×10-8).

Conclusions: We identified 1 novel candidate region associated with LVOTDs and report on several additional regions with suggestive evidence for association with CTD and LVOTD. These studies were constrained by the relatively small samples sizes and thus have limited power to detect small to moderate associations. Approaches that minimize the multiple testing burden (eg, gene or pathway based) may, therefore, be required to uncover common variants contributing to the risk of these relatively rare conditions.

Keywords: epidemiology; genome-wide association study; heart defects, congenital; polymorphism, single nucleotide.

Publication types

  • Meta-Analysis

MeSH terms

  • Cohort Studies
  • Databases, Factual
  • Female
  • Gene Frequency
  • Genome-Wide Association Study*
  • Genotype
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / pathology
  • Humans
  • Introns
  • Male
  • Membrane Proteins / genetics
  • Polymorphism, Single Nucleotide


  • MGAT4D protein, human
  • Membrane Proteins