Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries
Authors: Škorić-Milosavljević Doris , Tadros Rafik , Bosada Fernanda M. , Tessadori Federico , van Weerd Jan Hendrik , Woudstra Odilia I. , Tjong Fleur V.Y. , Lahrouchi Najim , Bajolle Fanny , Cordell Heather J. , Agopian A.J. , Blue Gillian M. , Barge-Schaapveld Daniela Q.C.M. , Gewillig Marc , Preuss Christoph , Lodder Elisabeth M. , Barnett Phil , Ilgun Aho , Beekman Leander , van Duijvenboden Karel , Bokenkamp Regina , Müller-Nurasyid Martina ,   KORA-Study Group, Vliegen Hubert W. , Konings Thelma C. , van Melle Joost P. , van Dijk Arie P.J. , van Kimmenade Roland R.J. , Roos-Hesselink Jolien W. , Sieswerda Gertjan T. , Meijboom Folkert , Abdul-Khaliq Hashim , Berger Felix , Dittrich Sven , Hitz Marc-Phillip , Moosmann Julia , Riede Frank-Thomas , Schubert Stephan , Galan Pilar , Lathrop Mark , Munter Hans M. , Al-Chalabi Ammar , Shaw Christopher E. , Shaw Pamela J. , Morrison Karen E. , Veldink Jan H. , van den Berg Leonard H. , Evans Sylvia , Nobrega Marcelo A. , Aneas Ivy , Radivojkov-Blagojević Milena , Meitinger Thomas , Oechslin Erwin , Mondal Tapas , Bergin Lynn , Smythe John F. , Altamirano-Diaz Luis , Lougheed Jane , Bouma Berto J. , Chaix Marie-A. , Kline Jennie , Bassett Anne S. , Andelfinger Gregor , van der Palen Roel L.F. , Bouvagnet Patrice , Clur Sally-Ann B. , Breckpot Jeroen , Kerstjens-Frederikse Wilhelmina S. , Winlaw David S. , Bauer Ulrike M.M. , Mital Seema , Goldmuntz Elizabeth , Keavney Bernard , Bonnet Damien , Mulder Barbara J. , Tanck Michael W.T. , Bakkers Jeroen , Christoffels Vincent M. , Boogerd Cornelis J. , Postma Alex V. , Bezzina Connie R. 
Published: December 2021

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.