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

Doris Škorić-Milosavljević, Rafik Tadros, KORA-Study Group, Fernanda M. Bosada, Federico Tessadori, Jan Hendrik van Weerd, Odilia I. Woudstra, Fleur V.Y. Tjong, Najim Lahrouchi, Fanny Bajolle, Heather J. Cordell, A. J. Agopian, Gillian M. Blue, Daniela Q.C.M. Barge-Schaapveld, Marc Gewillig, Christoph Preuss, Elisabeth M. Lodder, Phil Barnett, Aho Ilgun, Leander BeekmanKarel van Duijvenboden, Regina Bokenkamp, Martina Müller-Nurasyid, Hubert W. Vliegen, Thelma C. Konings, Joost P. van Melle, Arie P.J. van Dijk, Roland R.J. van Kimmenade, Jolien W. Roos-Hesselink, Gertjan T. Sieswerda, Folkert Meijboom, Hashim Abdul-Khaliq, Felix Berger, Sven Dittrich, Marc Phillip Hitz, Julia Moosmann, Frank Thomas Riede, Stephan Schubert, Pilar Galan, Mark Lathrop, Hans M. Munter, Ammar Al-Chalabi, Christopher E. Shaw, Pamela J. Shaw, Karen E. Morrison, Jan H. Veldink, Leonard H. van den Berg, Sylvia Evans, Marcelo A. Nobrega, Ivy Aneas, Milena Radivojkov-Blagojević

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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.

Original languageEnglish
Pages (from-to)166-180
Number of pages15
JournalCirculation Research
Issue number2
Publication statusPublished - 21 Jan 2022

Bibliographical note

Sources of Funding
This work has been funded by the Dutch Heart Foundation (CVON project 2014-18 CONCOR-genes) (to B.J. Bouma, C.R. Bezzina, J. Bakkers, M.W.T. Tanck, and V.M. Christoffels), a research grant from the Children’s Heart Foundation (to C.R. Bezzina) and by Foundation Leducq (to V.M. Christoffels). R. Tadros received support from the Canadian Heart Rhythm Society’s George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair and is currently a clinical research scholar of the Fonds de Recherche du Québec—Santé. F. Bajolle is funded by the Assistance Publique – Hôpitaux de Paris (APHP). G.M. Blue is supported by a Heart Foundation Postdoctoral Fellowship (101894). The work of E.M. Lodder is partly financed by the Dutch Research Council (NWO) through the NWO Talent Scheme VIDI-91718361 and the CVON RESCUED project. M. Müller-Nurasyid is supported by the department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany. P.J. Shaw is supported as an NIHR Senior Investigator and by the Sheffield NIHR Biomedical Research Centre. E. Oechslin currently holds the Bitove Family Professorship of Adult Congenital Heart Disease. Collection of the samples provided by J. Kline was supported by NIH grant RO1HL-08146 from National Heart, Lung, and Blood Institute (NHLBI) to Dorothy Warburton and Mike Wigler. The sequencing for this work was supported by a grant to the Baylor-Hopkins Center for Mendelian Genomics (5UM1HG006542) from National Human Genome Research Institute (NHGRI) and NHLBI. A.S. Bassett received support for this study from research grants from the Canadian Institutes of Health Research (CIHR) (MOP-93722) and the University of Toronto McLaughlin Centre. A.S. Bassett holds the Dalglish Chair in 22q11.2 Deletion Syndrome at the University of Toronto and University Health Network. R.L.F. van der Palen is supported by The Dutch Heart Foundation (grant number 2014T087). J. Breckpot is supported by a Senior Clinical Investigator Fellowship of the FWO - Flanders. S. Mital is supported by Canadian Institutes of Health Research, under the frame of ERA PerMed, Heart and Stroke Foundation of Canada, Ted Rogers Centre for Heart Research. E. GoldmuntzS received support for this study from research grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD070454); the NHLBI (P50-HL74731), including the Pediatric Cardiac Genomics Consortium (PCGC) (U01-HL098188, U01HL131003, U01-HL098147, U01-HL098153, U01-HL098163, U01-HL098123, U01-HL098162, U01-HL-09003); the NHGRI (U54HG006504); the National Center for Research Resources (M01-RR-000240, RR024134; now the National Center for Advancing Translational Sciences, grant number UL1TR000003). B. Keavney is funded by a British Heart Foundation Personal Chair. D. Bonnet is funded by Association pour la Recherche en Cardiologie du Fœtus à l’Adulte (ARCFA) and Fondation Cœur et Artères. The MINE study (J.H. Veldink) has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement n° 772376 – EScORIAL). The collaboration project is co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from Funding for the project was provided by the Wellcome Trust under award 076113, 085475, and 090355. This work was supported by the Competence Network for Congenital Heart Defects, which has received funding from the Federal Ministry of Education and Research, grant number 01GI0601 (until 2014), and the DZHK (German Centre for Cardiovascular Research; as of 2015). A subset of the data used in the replication cohort were generated by the PCGC, under the auspices of the NHLBI’s Bench to Bassinet Program (dbGaP Study Accession: phs001194.v2.p2). The PCGC program is funded by the NHLBI, National Institutes of Health, U.S. Department of Health and Human Services through grants UM1HL128711, UM1HL098162, UM1HL098147, UM1HL098123, UM1HL128761, and U01HL131003. This article was not prepared in collaboration with investigators of the PCGC, has not been reviewed and/or approved by the PCGC, and does not necessarily reflect the opinions of the PCGC investigators or the NHLBI.

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