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

Abstract

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.

Figure 1

Schematic of the five independent cohorts and summary of which cohorts were analyzed in each meta-analysis.

Figure 2

Regional association plots for the meta-analysis between LVOTDs and: A) maternal SNPs near rs55788414 B) inherited SNPs near rs72820264. Each pane shows the association statistic from the meta-analysis (−log₁₀ p) on the left y-axis for the variant with the lowest combined p-value (purple diamond) and nearby markers (circles). The red shading indicates the amount of linkage disequilibrium (r²) between this variant and the nearby markers. The right y-axis indicates recombination rates from 1000 Genomes CEU data (blue lines). The x-axis indicates the chromosomal position (hg19) and the location of nearby genes.