Paediatrics Publications

Title

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

Authors

Doris Škorić-Milosavljević, Amsterdam UMC - University of Amsterdam
Rafik Tadros, Amsterdam UMC - University of Amsterdam
Fernanda M. Bosada, Amsterdam UMC - University of Amsterdam
Federico Tessadori, University Medical Center Utrecht
Jan Hendrik Van Weerd, Amsterdam UMC - University of Amsterdam
Odilia I. Woudstra, Amsterdam UMC - University of Amsterdam
Fleur V.Y. Tjong, Amsterdam UMC - University of Amsterdam
Najim Lahrouchi, Amsterdam UMC - University of Amsterdam
Fanny Bajolle, Hôpital Necker Enfants Malades
Heather J. Cordell, Newcastle University
A. J. Agopian, University of Texas School of Public Health
Gillian M. Blue, The University of Sydney School of Medicine
Daniela Q.C.M. Barge-Schaapveld, Leids Universitair Medisch Centrum
Marc Gewillig, KU Leuven
Christoph Preuss, CHU Sainte-Justine - Le Centre Hospitalier Universitaire Mère-Enfant
Elisabeth M. Lodder, Amsterdam UMC - University of Amsterdam
Phil Barnett, Amsterdam UMC - University of Amsterdam
Aho Ilgun, Amsterdam UMC - University of Amsterdam
Leander Beekman, Amsterdam UMC - University of Amsterdam
Karel Van Duijvenboden, Amsterdam UMC - University of Amsterdam
Regina Bokenkamp, Leids Universitair Medisch Centrum
Martina Müller-Nurasyid, Helmholtz Center Munich German Research Center for Environmental Health
Hubert W. Vliegen, Leids Universitair Medisch Centrum
Thelma C. Konings, Amsterdam UMC - University of Amsterdam
Joost P. Van Melle, Universitair Medisch Centrum Groningen
Arie P.J. Van Dijk, Radboud University Medical Center
Roland R.J. Van Kimmenade, Radboud University Medical Center
Jolien W. Roos-Hesselink, Erasmus MC
Gertjan T. Sieswerda, University Medical Center Utrecht

Document Type

Article

Publication Date

1-21-2022

Journal

Circulation Research

Volume

130

Issue

2

First Page

166

Last Page

180

URL with Digital Object Identifier

10.1161/CIRCRESAHA.120.317107

Abstract

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.

This document is currently not available here.

Share

COinS