Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot

Abstract

We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10−7) and replicated convincingly (P = 3.9 × 10−5) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10−11 in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10−7) and replicated convincingly (P = 1.2 × 10−5) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10−11 in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF.

Association analysis identifies new risk loci for congenital heart disease in Chinese populations

“…Cordell et al 11 published two studies of CHD in Europeans, one of them recruited multiple CHD phenotypes and the other one only included TOF cases 12 . Using their existing GWA scan data, we attempted to investigate the associations of the four SNPs we identified and the CHD risk in Europeans.…”

“…The discovery cohorts of the two European GWASs comprise CHD cases of multiple phenotypes and TOF cases 11,12 . All cases are self-reported European Caucasian ancestry recruited from multiple centres in the UK and from centres in Leuven, Belgium, Erlangen, Germany and Sydney, Australia.…”

“…All diagnoses were established by CHD specialists at the contributing centres, and cases were classified using European Paediatric Cardiac Codes. Cases exhibiting clinical features of recognized malformation syndromes, multiple developmental abnormalities or learning difficulties were excluded from the study 11,12 . After stringent quality control, we analysed the associations of two typed SNPs (rs1400558 and rs490514) and the risk of CHD in the current data set which consisted of 2,111 unrelated CHD cases (ASD: 340; VSD: 191; TGA: 207; conotruncal malformations: 151 and left-sided malformations: 387; TOF: 835) and 5,159 controls.…”

“…To date, several genome-wide association studies (GWASs) have achieved success in deciphering the genetic basis of CHD [10][11][12] . One study on European Caucasians reported that single nucleotide polymorphisms (SNPs) at chromosome 4p16 were associated with the risk of atrial septal defect (ASD), but not other subtypes 11 .…”

Glypican4 promotes cardiac specification and differentiation by attenuating canonical Wnt and Bmp signaling

“…Congenital heart defects have been reported in patients with autosomal-recessive omodysplasia, which is caused by mutations in GPC6. A recent whole-genome association study identified a single nucleotide polymorphism in the GPC5 gene located on chromosome 13q that was associated with Tetralogy of Fallot (TOF), a severe congenital heart defect (Cordell et al, 2013). Several individual cases with 13q deletions that include the GPC5 gene have been reported in patients with TOF (Quelin et al, 2009).…”