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Skoric-Milosavljevic, D.* ; Tadros, R.* ; Bosada, F.M.* ; Tessadori, F.* ; van Weerd, J.H.* ; Woudstra, O.I.* ; Tjong, F.V.Y.* ; Lahrouchi, N.* ; Bajolle, F.* ; Cordell, H.J.* ; Agopian, A.J.* ; Blue, G.M.* ; Barge-Schaapveld, D.Q.* ; Gewillig, M.H.* ; Preuss, C.* ; Lodder, E.M.* ; Barnett, P.* ; Ilgun, A.* ; Beekman, L.* ; van Duijvenboden, K.* ; Bokenkamp, R.* ; Müller-Nurasyid, M. ; Vliegen, H.W.* ; Konings, T.C.* ; van Melle, J.P.* ; van Dijk, A.* ; van Kimmenade, R.R.* ; Roos-Hesselink, J.W.* ; Sieswerda, G.* ; Meijboom, F.* ; Abdul-Khaliq, H.* ; Berger, F.* ; Dittrich, S.* ; Hitz, M.P.* ; Moosmann, J.* ; Riede, F.T.* ; Schubert, S.* ; Galan, P.* ; Lathrop, G.M.* ; Munter, H.M.* ; Al-Chalabi, A.* ; Shaw, C.E.* ; Shaw, P.J.* ; Morrison, K.E.* ; Veldink, J.H.* ; van den Berg, L.H.* ; Evans, S.M.* ; Nobrega, M.A.* ; Aneas, I.* ; Radivojkov-Blagojevic, M. ; Meitinger, T. ; Oechslin, E.* ; Mondal, T.* ; Bergin, M.L.* ; Smythe, J.F.* ; Altamirano-Diaz, L.* ; Lougheed, J.* ; Bouma, B.J.* ; Chaix, M.A.* ; Kline, J.* ; Bassett, A.S.* ; Andelfinger, G.* ; van der Palen, R.L.* ; Bouvagnet, P.* ; Clur, S.B.* ; Breckpot, J.* ; Kerstjens-Frederikse, W.S.* ; Winlaw, D.S.* ; Bauer, U.* ; Mital, S.* ; Goldmuntz, E.* ; Keavney, B.D.* ; Bonnet, D.* ; Mulder, B.J.* ; Tanck, M.* ; Bakkers, J.* ; Christoffels, V.M.* ; Boogerd, C.J.* ; Postma, A.V.* ; Bezzina, C.R.*

Common genetic variants contribute to risk of transposition of the great arteries.

Circ. Res. 130, 166-180 (2021)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Congenital Heart Disease ; Genome-wide Association Study ; Single Nucleotide Polymorphism ; Transposition Of Great Vessels ; Wnt-5a Protein; Congenital Heart-disease; Genome-wide Association; Hypoplastic Left-heart; Of-function Mutations; Wnt5a Mutations; Zic3 Mutations; De-novo; Defects; Malformations; Heritability
ISSN (print) / ISBN 0009-7330
e-ISSN 1524-4571
Journal Circulation Research
Quellenangaben Volume: 130, Issue: 2, Pages: 166-180 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Human Genetics (IHG)
Grants Canadian Institutes of Health Research (CIHR)
University of Toronto McLaughlin Centre
Dutch Heart Foundation
NHLBI
National Human Genome Research Institute (NHGRI)
NIH from National Heart, Lung, and Blood Institute (NHLBI)
Children's Heart Foundation
Foundation Leducq
Canadian Heart Rhythm Society's George Mines Award
European Society of Cardiology research award
Philippa and Marvin Carsley Cardiology Chair
Assistance Publique Hopitaux de Paris (APHP)
Heart Foundation Postdoctoral Fellowship
Dutch Research Council (NWO) through the NWO Talent Scheme
Dutch Research Council (NWO) through CVON RESCUED project
department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
NIHR
Sheffield NIHR Biomedical Research Centre
FWO-Flanders
Canadian Institutes of Health Research
Munich Center of Health Sciences (MC-Health)
Ludwig-Maximilians-Universitat, as part of LMUinnovativ
Wellcome Trust
Competence Network for Congenital Heart Defects from the Federal Ministry of Education and Research
DZHK (German Centre for Cardiovascular Research)
State of Bavaria
Helmholtz Zentrum Munchen -German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
Healthsimilar toHolland
Heart and Stroke Foundation of Canada
Ted Rogers Centre for Heart Research
Eunice Kennedy Shriver National Institute of Child Health and Human Development
NHGRI
National Center for Research Resources
National Center for Advancing Translational Sciences
British Heart Foundation
Association pour la Recherche en Cardiologie du Foetus a l'Adulte (ARCFA)
Fondation Coeur et Arteres
European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme
PPP Allowance
NHLBI, National Institutes of Health, U.S. Department of Health and Human Services