Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16

Abstract

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10⁻⁷) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10⁻⁵; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 × 10⁻¹⁰). Genotype accounted for ~9% of the population-attributable risk of ASD.

Figure 1

LocusZoom plot of region of association with ASD at chromosome 4p16. Genes and ESTs within the region are shown in the lower panel, and the unbroken blue line indicates recombination rate within the region. Each filled circle represents the P-value for one SNP in the discovery cohort, with the top SNP rs870142 shown in purple and SNPs in the region colour-coded depending upon their degree of correlation (r²) with rs870142 (as estimated internally by LocusZoom on the basis of CEU HapMap haplotypes). The P-values for the three SNPs in this region when analysed in the combined discovery and replication cohorts are shown as filled squares.