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

Skoric-Milosavljevic D, Tadros R, Bosada FM, Tessadori F, Van Weerd JH, Woudstra O, Tjong FVY, Lahrouchi N, Bajolle F, Cordell HJ, Agopian AJ, Blue GM, Barge-Schaapveld DQCM, Gewillig M, Preuss C, Lodder EM, Barnett P, Ilgun A, Beekman L, Van Duijvenboden K, Bokenkamp R, Muller-Nurasyid M, Vliegen HW, Konings TC, Van Melle JP, Van Dijk APJ, Van Kimmenade RRJ, Roos-Hesselink JW, Sieswerda G, Meijboom F, Abdul-Khaliq H, Berger F, Dittrich S, Hitz MP, Moosmann J, Riede FT, Schubert S, Galan P, Lathrop M, Munter HM, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Veldink JH, Van Den Berg LH, Evans S, Nobrega MA, Aneas I, Radivojkov-Blagojevic M, Meitinger T, Oechslin E, Mondal T, Bergin ML, Smythe JF, Altamirano-Diaz L, Lougheed J, Bouma BJ, Chaix MA, Kline J, Bassett AS, Andelfinger G, Van Der Palen RLF, Bouvagnet P, Clur SAB, Breckpot J, Kerstjens-Frederikse WS, Winlaw DS, Bauer UMM, Mital S, Goldmuntz E, Keavney B, Bonnet D, Mulder BJ, Tanck MWT, Bakkers J, Christoffels VM, Boogerd CJ, Postma A, Bezzina CR (2022)

Publication Type: Journal article

Publication year: 2022


Book Volume: 130

Pages Range: 166-180

Journal Issue: 2

DOI: 10.1161/CIRCRESAHA.120.317107


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(-10), 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(-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.

Authors with CRIS profile

Involved external institutions

University of Amsterdam NL Netherlands (NL) Hubrecht Institute NL Netherlands (NL) Universiteit Utrecht (UU) / Utrecht University NL Netherlands (NL) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) DE Germany (DE) Université de Montréal CA Canada (CA) Columbia University US United States (USA) (US) University of Toronto CA Canada (CA) Hôpital Necker-Enfants malades FR France (FR) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra NL Netherlands (NL) University of Texas Health Science Center at Houston (UTHealth) US United States (USA) (US) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Charité - Universitätsmedizin Berlin DE Germany (DE) Newcastle University GB United Kingdom (GB) Westmead Hospital AU Australia (AU) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Leiden University Medical Center NL Netherlands (NL) Vrije Universiteit Amsterdam (VU) / University Amsterdam NL Netherlands (NL) University of Groningen / Rijksuniversiteit Groningen NL Netherlands (NL) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) NL Netherlands (NL) Maastricht University NL Netherlands (NL) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam NL Netherlands (NL) Universitätsklinikum des Saarlandes (UKS) DE Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE) Universität Leipzig DE Germany (DE) University of Paris 13 - Paris-Nord / Université Paris XIII Paris-Nord FR France (FR) McGill University CA Canada (CA) King’s College London GB United Kingdom (GB) University of Sheffield GB United Kingdom (GB) Queen's University GB United Kingdom (GB) University of California, San Diego US United States (USA) (US) University of Chicago US United States (USA) (US) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Kingston General Hospital (KGH) CA Canada (CA) Western University CA Canada (CA) Children's Hospital of Eastern Ontario (CHEO) / Centre hospitalier pour enfants de l'est de l'Ontario CA Canada (CA) CHU Martinique MQ Martinique (MQ) Academic Medical Centre / Academisch Medisch Centrum (AMC) NL Netherlands (NL) Children's Hospital of Philadelphia US United States (USA) (US) University of Manchester GB United Kingdom (GB)

How to cite


Skoric-Milosavljevic, D., Tadros, R., Bosada, F.M., Tessadori, F., Van Weerd, J.H., Woudstra, O.,... Bezzina, C.R. (2022). Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries. Circulation Research, 130(2), 166-180.


Skoric-Milosavljevic, Doris, et al. "Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries." Circulation Research 130.2 (2022): 166-180.

BibTeX: Download