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

Rationale: 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.

Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA.

Methods And Results: 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, OR=0.69 per C allele). 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). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of , 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 . Genomic and functional data support a causal role of at the locus.

Citing Articles

Beyond genomic studies of congenital heart defects through systematic modelling and phenotyping.

Henderson D, Alqahtani A, Chaudhry B, Cook A, Eley L, Houyel L Dis Model Mech. 2024; 17(11).

PMID: 39575509 PMC: 11603121. DOI: 10.1242/dmm.050913.

A validated heart-specific model for splice-disrupting variants in childhood heart disease.

Lesurf R, Breckpot J, Bouwmeester J, Hanafi N, Jain A, Liang Y Genome Med. 2024; 16(1):119.

PMID: 39402625 PMC: 11476204. DOI: 10.1186/s13073-024-01383-8.

Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants.

Qiao L, Welch C, Hernan R, Wynn J, Krishnan U, Zalieckas J Am J Hum Genet. 2024; 111(11):2362-2381.

PMID: 39332409 PMC: 11568762. DOI: 10.1016/j.ajhg.2024.08.024.

Complex trait associations in rare diseases and impacts on Mendelian variant interpretation.

Smail C, Ge B, Keever-Keigher M, Schwendinger-Schreck C, Cheung W, Johnston J Nat Commun. 2024; 15(1):8196.

PMID: 39294130 PMC: 11411080. DOI: 10.1038/s41467-024-52407-1.

Pathogenesis and Surgical Treatment of Dextro-Transposition of the Great Arteries (D-TGA): Part II.

Zubrzycki M, Schramm R, Costard-Jackle A, Morshuis M, Gummert J, Zubrzycka M J Clin Med. 2024; 13(16).

PMID: 39200964 PMC: 11355351. DOI: 10.3390/jcm13164823.

References

Pennacchio L, Ahituv N, Moses A, Prabhakar S, Nobrega M, Shoukry M . In vivo enhancer analysis of human conserved non-coding sequences. Nature. 2006; 444(7118):499-502. DOI: 10.1038/nature05295. View

Ihara D, Watanabe Y, Seya D, Arai Y, Isomoto Y, Nakano A . Expression of Hey2 transcription factor in the early embryonic ventricles is controlled through a distal enhancer by Tbx20 and Gata transcription factors. Dev Biol. 2020; 461(2):124-131. DOI: 10.1016/j.ydbio.2020.02.001. View

Roifman M, Marcelis C, Paton T, Marshall C, Silver R, Lohr J . De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype. Clin Genet. 2014; 87(1):34-41. DOI: 10.1111/cge.12401. View

Machiela M, Chanock S . LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics. 2015; 31(21):3555-7. PMC: 4626747. DOI: 10.1093/bioinformatics/btv402. View

Barnes R, Harris I, Jaehnig E, Sauls K, Sinha T, Rojas A . MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1. Development. 2016; 143(5):774-9. PMC: 4813332. DOI: 10.1242/dev.126383. View

Lee S, Wray N, Goddard M, Visscher P . Estimating missing heritability for disease from genome-wide association studies. Am J Hum Genet. 2011; 88(3):294-305. PMC: 3059431. DOI: 10.1016/j.ajhg.2011.02.002. View

Digilio M, Casey B, Toscano A, Calabro R, Pacileo G, Marasini M . Complete transposition of the great arteries: patterns of congenital heart disease in familial precurrence. Circulation. 2001; 104(23):2809-14. DOI: 10.1161/hc4701.099786. View

Goldmuntz E, Bamford R, Karkera J, dela Cruz J, Roessler E, Muenke M . CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle. Am J Hum Genet. 2002; 70(3):776-80. PMC: 384955. DOI: 10.1086/339079. View

Josifova D, Monroe G, Tessadori F, de Graaff E, Van der Zwaag B, Mehta S . Heterozygous KIDINS220/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity. Hum Mol Genet. 2016; 25(11):2158-2167. DOI: 10.1093/hmg/ddw082. View

10.

Osterwalder M, Barozzi I, Tissieres V, Fukuda-Yuzawa Y, Mannion B, Afzal S . Enhancer redundancy provides phenotypic robustness in mammalian development. Nature. 2018; 554(7691):239-243. PMC: 5808607. DOI: 10.1038/nature25461. View

11.

Cohen E, Miller M, Wang Z, Moon R, Morrisey E . Wnt5a and Wnt11 are essential for second heart field progenitor development. Development. 2012; 139(11):1931-40. PMC: 3347685. DOI: 10.1242/dev.069377. View

12.

Boogerd C, Zhu X, Aneas I, Sakabe N, Zhang L, Sobreira D . Tbx20 Is Required in Mid-Gestation Cardiomyocytes and Plays a Central Role in Atrial Development. Circ Res. 2018; 123(4):428-442. PMC: 6092109. DOI: 10.1161/CIRCRESAHA.118.311339. View

13.

Li Y, Klena N, Gabriel G, Liu X, Kim A, Lemke K . Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature. 2015; 521(7553):520-4. PMC: 4617540. DOI: 10.1038/nature14269. View

14.

Niemi M, Martin H, Rice D, Gallone G, Gordon S, Kelemen M . Common genetic variants contribute to risk of rare severe neurodevelopmental disorders. Nature. 2018; 562(7726):268-271. PMC: 6726472. DOI: 10.1038/s41586-018-0566-4. View

15.

Bakker M, Boukens B, Mommersteeg M, Brons J, Wakker V, Moorman A . Transcription factor Tbx3 is required for the specification of the atrioventricular conduction system. Circ Res. 2008; 102(11):1340-9. DOI: 10.1161/CIRCRESAHA.107.169565. View

16.

Costain G, Lionel A, Ogura L, Marshall C, Scherer S, Silversides C . Genome-wide rare copy number variations contribute to genetic risk for transposition of the great arteries. Int J Cardiol. 2015; 204:115-21. DOI: 10.1016/j.ijcard.2015.11.127. View

17.

Grant C, Bailey T, Noble W . FIMO: scanning for occurrences of a given motif. Bioinformatics. 2011; 27(7):1017-8. PMC: 3065696. DOI: 10.1093/bioinformatics/btr064. View

18.

Ruiz-Villalba A, Mattiotti A, Gunst Q, Cano-Ballesteros S, van den Hoff M, Ruijter J . Reference genes for gene expression studies in the mouse heart. Sci Rep. 2017; 7(1):24. PMC: 5428317. DOI: 10.1038/s41598-017-00043-9. View

19.

Westra H, Peters M, Esko T, Yaghootkar H, Schurmann C, Kettunen J . Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013; 45(10):1238-1243. PMC: 3991562. DOI: 10.1038/ng.2756. View

20.

Sinha T, Li D, Theveniau-Ruissy M, Hutson M, Kelly R, Wang J . Loss of Wnt5a disrupts second heart field cell deployment and may contribute to OFT malformations in DiGeorge syndrome. Hum Mol Genet. 2014; 24(6):1704-16. PMC: 4381755. DOI: 10.1093/hmg/ddu584. View