Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16.
Cordell HJ., Bentham J., Topf A., Zelenika D., Heath S., Mamasoula C., Cosgrove C., Blue G., Granados-Riveron J., Setchfield K., Thornborough C., Breckpot J., Soemedi R., Martin R., Rahman TJ., Hall D., van Engelen K., Moorman AFM., Zwinderman AH., Barnett P., Koopmann TT., Adriaens ME., Varro A., George AL., dos Remedios C., Bishopric NH., Bezzina CR., O'Sullivan J., Gewillig M., Bu'Lock FA., Winlaw D., Bhattacharya S., Devriendt K., Brook JD., Mulder BJM., Mital S., Postma AV., Lathrop GM., Farrall M., Goodship JA., Keavney BD.
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.