Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

Abstract

Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Methods: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). Results: SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.

Dextro-transposition of the great arteries in one twin: case reports and literature review

“…Lee et al (20) suggested chromosomal microarray analysis as an effective tool to detect chromosomal copy number variation in fetuses with D-TGA and to improve prenatal counseling, postnatal management, and neurodevelopmental outcomes. Skoric-Milosavljevic et al (21) identified a susceptibility locus at 3p14.3, which is known for its important role in cardiac development. Of note, there exist suspect that D-TGA is polygenic inheritance (22,23).…”

Common genetic variants improve risk stratification after the atrial switch operation for transposition of the great arteries

“…Genotypic data were generated using the Illumina Human-OmniExpress beadchip (genotyping at ~700.000 SNPs) and quality control was performed as described previously [16] (Supplementary methods).…”

Noncanonical Splice-Altering Variants: Hidden Culprits of Congenital Heart Disease

“…10 Further, contributions from common variants toward the development of certain CHD subtypes, including transposition of the great arteries and other complex disease, have been highlighted. 11,12 In this edition of Circulation: Genomics and Precision Medicine, Jang et al 13 evaluate noncoding variants near canonical splice sites and their potential to disrupt RNA processing resulting in CHD. Using a combination of computational and in vitro (minigene) assays, they identified 53 de novo variants and 74 rare variants resulting in aberrant splicing in a cohort of 4474 CHD probands from the Pediatric Cardiac Genomics Consortium.…”

“…A significant portion of the remaining unsolved cases are hypothesized to result from complex interactions between multiple genetic/epigenetic changes and factors affecting the fetal-placental-maternal environment. Polygenic contributions and the risks associated with disease development 11 and immediate postoperative and long-term outcomes 18 in patients with CHD (ie, polygenic risk scores) are emerging as additional disease contributors; and the large, genotype-phenotype cohorts required to facilitate studies with appropriate statistical power to identify significant disease associations are being further refined. 19 However, there is still much work to be done in understanding the dark matter of the genome, that is, the noncoding regions, and the likely contribution of these hidden culprits to CHD development.…”

“…Further, contributions from common variants toward the development of certain CHD subtypes, including transposition of the great arteries and other complex disease, have been highlighted. 11,12…”