Genome-wide association study of maternal and inherited loci for conotruncal heart defects

Abstract

Conotruncal and related heart defects (CTDs) are a group of serious and relatively common birth defects. Although both maternal and inherited genotypes are thought to play a role in the etiology of CTDs, few specific genetic risk factors have been identified. To determine whether common variants acting through the genotype of the mother (e.g. via an in utero effect) or the case are associated with CTDs, we conducted a genome-wide association study of 750 CTD case-parent triads, with follow-up analyses in 358 independent triads. Log-linear analyses were used to assess the association of CTDs with the genotypes of both the mother and case. No association achieved genomewide significance in either the discovery or combined (discovery+follow-up) samples. However, three loci with p-values suggestive of association (p<10-5) in the discovery sample had p-values <0.05 in the follow-up sample and p-values in the combined data that were lower than in the discovery sample. These included suggestive association with an inherited intergenic variant at 20p12.3 (rs6140038, combined p = 1.0 × 10(-5)) and an inherited intronic variant in KCNJ4 at 22q13.1 (rs2267386, combined p = 9.8 × 10(-6)), as well as with a maternal variant in SLC22A24 at 11q12.3 (rs11231379, combined p = 4.2 × 10(-6)). These observations suggest novel candidate loci for CTDs, including loci that appear to be associated with the risk of CTDs via the maternal genotype, but further studies are needed to confirm these associations.

Figure 1. Loci showing suggestive associations with conotruncal malformations in the discovery sample.

A) SNPs in SLC22A24 B) SNPs near FHIT C) rs2267386 D) rs6140038. Each pane shows the log-linear model association statistic (−log₁₀ p) on the left y axis for the discovery sample variant with the highest regional value that was confirmed in our follow-up sample (purple diamond) and nearby markers (circles). Linkage disequilibrium (r²) between this variant and nearby markers is indicated by red shading and recombination rates across each region in 1000 Genomes CEU data are indicated by blue lines on the right y axis. The position on the chromosome (hg18) and the position of nearby genes is shown on the x-axis.