. 2022 Jan 21;130(2):166-180.

doi: 10.1161/CIRCRESAHA.120.317107. Epub 2021 Dec 10.

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

Doris Škorić-Milosavljević^#^{1

2}, Rafik Tadros^#^{1

3}, Fernanda M Bosada^#⁴, Federico Tessadori^#⁵, Jan Hendrik van Weerd⁴, Odilia I Woudstra^{1

6}, Fleur V Y Tjong¹, Najim Lahrouchi¹, Fanny Bajolle⁷, Heather J Cordell⁸, A J Agopian⁹, Gillian M Blue¹⁰, Daniela Q C M Barge-Schaapveld¹¹, Marc Gewillig¹², Christoph Preuss^{13

14}, Elisabeth M Lodder^{1

2}, Phil Barnett⁴, Aho Ilgun⁴, Leander Beekman¹, Karel van Duijvenboden⁴, Regina Bokenkamp¹⁵, Martina Müller-Nurasyid^{16

17

18}; KORA-Study Group; Hubert W Vliegen¹⁹, Thelma C Konings²⁰, Joost P van Melle²¹, Arie P J van Dijk²², Roland R J van Kimmenade^{22

23}, Jolien W Roos-Hesselink²⁴, Gertjan T Sieswerda⁶, Folkert Meijboom⁶, Hashim Abdul-Khaliq²⁵, Felix Berger^{26

27}, Sven Dittrich²⁸, Marc-Phillip Hitz^{29

30}, Julia Moosmann²⁸, Frank-Thomas Riede³¹, Stephan Schubert^{7

32}, Pilar Galan³³, Mark Lathrop³⁴, Hans M Munter³⁴, Ammar Al-Chalabi³⁵, Christopher E Shaw^{36

37}, Pamela J Shaw³⁸, Karen E Morrison³⁹, Jan H Veldink⁴⁰, Leonard H van den Berg⁴⁰, Sylvia Evans⁴¹, Marcelo A Nobrega⁴², Ivy Aneas⁴², Milena Radivojkov-Blagojević⁴³, Thomas Meitinger^{43

44}, Erwin Oechslin⁴⁵, Tapas Mondal⁴⁶, Lynn Bergin⁴⁷, John F Smythe⁴⁸, Luis Altamirano-Diaz⁴⁹, Jane Lougheed⁵⁰, Berto J Bouma¹, Marie-A Chaix³, Jennie Kline⁵¹, Anne S Bassett^{52

53}, Gregor Andelfinger¹³, Roel L F van der Palen¹⁵, Patrice Bouvagnet⁵⁴, Sally-Ann B Clur^{55

56}, Jeroen Breckpot^{5

57}, Wilhelmina S Kerstjens-Frederikse⁵⁸, David S Winlaw¹⁰, Ulrike M M Bauer⁵⁹, Seema Mital⁶⁰, Elizabeth Goldmuntz⁶¹, Bernard Keavney⁶², Damien Bonnet²⁶, Barbara J Mulder¹, Michael W T Tanck⁶³, Jeroen Bakkers⁶⁴, Vincent M Christoffels⁴, Cornelis J Boogerd⁵, Alex V Postma^#^{2

4}, Connie R Bezzina^#¹

Affiliations

¹ Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, The Netherlands (D.S.-M., R.T., O.I.W., F.V.Y.T., N.L., E.M.L., L.B., B.J.B., B.J.M., C.R.B.).
² Department of Human Genetics, Amsterdam University Medical Centers, The Netherlands (D.S.-M., E.M.L., A.V.P.).
³ Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada (R.T., M.-A.C.).
⁴ Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands (F.M.B., J.H.v.W., P.B., A.I., K.v.D., V.M.C., A.V.P.).
⁵ Hubrecht Institute-KNAW and University Medical Center Utrecht, the Netherlands (F.T., J.B., C.J.B.).
⁶ Department of Cardiology, University Medical Center Utrecht, The Netherlands (O.I.W., G.T.S., F.M.).
⁷ German Heart Center Berlin, Department of Congenital Heart Disease, Pediatric Cardiology, DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany (F.B., S.S.).
⁸ Population Health Sciences Institute, Newcastle University, Newcastle, United Kingdom (H.J.C.).
⁹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, UTHealth School of Public Health, Houston, TX (A.J.A.).
¹⁰ Heart Centre for Children, The Children's Hospital at Westmead and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Australia (G.M.B., D.S.W.).
¹¹ Department of Clinical Genetics, Leiden University Medical Center, The Netherlands (D.Q.C.M.B.-S.).
¹² University of Leuven, Belgium (M.G.).
¹³ Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Québec, Canada (C.P., G.A.).
¹⁴ The Jackson Laboratory, Bar Harbor, ME (C.P.).
¹⁵ Division of Pediatric Cardiology, Department of Pediatrics (R.B., R.L.F.v.d.P.), Leiden University Medical Center, The Netherlands.
¹⁶ Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany (M.M.-N.).
¹⁷ IBE, Faculty of Medicine, LMU Munich, Germany (M.M.-N.).
¹⁸ Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.M.-N.).
¹⁹ Department of Cardiology (H.W.V.), Leiden University Medical Center, The Netherlands.
²⁰ Department of Cardiology, Amsterdam University Medical Centers, VU Amsterdam, The Netherlands (T.C.K.).
²¹ Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.P.v.M.).
²² Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands (A.P.J.v.D., R.R.J.v.K.).
²³ Department of Cardiology, Maastricht University Medical Center, The Netherlands (R.R.J.v.K.).
²⁴ Department of Cardiology, Erasmus Medical Center, Erasmus University, Rotterdam, The Netherlands (J.W.R.-H.).
²⁵ Saarland University Medical Center, Department of Pediatric Cardiology, Homburg, Germany (H.A.-K.).
²⁶ Unité Médico-Chirurgicale de Cardiologie Congénitale et Pédiatrique, Centre de référence Malformations Cardiaques Congénitales Complexes - M3C, Hôpital Necker Enfants Malades, APHP and Université Paris Descartes, Sorbonne Paris Cité, Paris, France (F.B., D.B.).
²⁷ Charité, Universitätsmedizin Berlin, Department for Paediatric Cardiology, Germany (F.B.).
²⁸ Department of Pediatric Cardiology, Friedrich-Alexander-University of Erlangen-Nuernberg (FAU), Germany (S.D., J.M.).
²⁹ Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein/Campus Kiel, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (M.-P.H.).
³⁰ Department of Human Genetics, University Medical Center Schleswig-Holstein, Kiel, Germany (M.-P.H.).
³¹ Leipzig Heart Center, Department of Pediatric Cardiology, University of Leipzig, Germany (F.-T.R.).
³² Heart and Diabetes Center NRW, Center of Congenital Heart Disease, Ruhr-University of Bochum, Bad Oeynhausen, Germany (S.S.).
³³ Sorbonne Paris Nord (Paris 13) University, Inserm U1153, Inrae U1125, Cnam, Nutritional Epidemiology Research Team (EREN), Epidemiology and Statistics Research Center - University of Paris (CRESS), Bobigny, France (P.G.).
³⁴ McGill Genome Centre and Department of Human Genetics, McGill University, Montreal, Québec, Canada (M.L., H.M.M.).
³⁵ Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King's College London, United Kingdom (A.A.-C.).
³⁶ United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom (C.E.S.).
³⁷ Centre for Brain Research, University of Auckland, New Zealand (C.E.S.).
³⁸ Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield and NIHR Sheffield Biomedical Research Centre for Translational Neuroscience, United Kingdom (P.J.S.).
³⁹ Faculty of Medicine Health & Life Sciences, Queens University Belfast, United Kingdom (K.E.M.).
⁴⁰ Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands (J.H.V., L.H.v.d.B.).
⁴¹ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego (S.E.).
⁴² Department of Human Genetics, University of Chicago, IL (M.A.N., I.A.).
⁴³ Helmholtz Zentrum Munich, Institut of Human Genetics, Neuherberg, Germany (M.R.-B., T.M.).
⁴⁴ Division of Cardiology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada (T.M.).
⁴⁵ Peter Munk Cardiac Center, Toronto Congenital Cardiac Centre for Adults and University of Toronto, Canada (E.O.).
⁴⁶ DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (T.M.).
⁴⁷ Division of Cardiology, Department of Medicine, London Health Sciences Centre, ON, Canada (L.B.).
⁴⁸ Division of Cardiology, Department of Pediatrics, Kingston General Hospital, ON, Canada (J.F.S.).
⁴⁹ Western University, Ontario, Canada (L.A.-D.).
⁵⁰ Division of Cardiology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada (J.L.).
⁵¹ Department of Epidemiology, Mailman School of Public Health, Columbia University, NY (J.K.).
⁵² Clinical Genetics Research Program, Centre for Addiction and Mental Health (A.S.B.).
⁵³ Department of Psychiatry, University of Toronto, Toronto General Hospital, University Health Network, Ontario, Canada (A.S.B.).
⁵⁴ CPDPN, Hôpital MFME, CHU Martinique, Fort de France, Martinique, France (P.B.).
⁵⁵ Department of Pediatric Cardiology, Emma Children's Hospital Amsterdam University Medical Centers (AMC), The Netherlands (S.-A.B.C.).
⁵⁶ Centre for Congenital Heart Disease Amsterdam-Leiden (CAHAL) (S.-A.B.C.).
⁵⁷ Center for Human Genetics University Hospitals KU Leuven, Belgium (J.B.).
⁵⁸ Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, The Netherlands (W.S.K.-F.).
⁵⁹ National Register for Congenital Heart Defects, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (U.M.M.B.).
⁶⁰ Hospital for Sick Children, University of Toronto, Ontario, Canada (S.M.).
⁶¹ Division of Cardiology, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (E.G.).
⁶² Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester and Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, United Kingdom (B.K.).
⁶³ Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health (APH), Amsterdam University Medical Centers, University of Amsterdam, The Netherlands (M.W.T.T.).
⁶⁴ Division of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, the Netherlands (J.B.).

^# Contributed equally.

PMID: 34886679
PMCID: PMC8768504
DOI: 10.1161/CIRCRESAHA.120.317107

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

Doris Škorić-Milosavljević et al. Circ Res. 2022.

. 2022 Jan 21;130(2):166-180.

doi: 10.1161/CIRCRESAHA.120.317107. Epub 2021 Dec 10.

Authors

Affiliations

¹ Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, The Netherlands (D.S.-M., R.T., O.I.W., F.V.Y.T., N.L., E.M.L., L.B., B.J.B., B.J.M., C.R.B.).
² Department of Human Genetics, Amsterdam University Medical Centers, The Netherlands (D.S.-M., E.M.L., A.V.P.).
³ Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada (R.T., M.-A.C.).
⁴ Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands (F.M.B., J.H.v.W., P.B., A.I., K.v.D., V.M.C., A.V.P.).
⁵ Hubrecht Institute-KNAW and University Medical Center Utrecht, the Netherlands (F.T., J.B., C.J.B.).
⁶ Department of Cardiology, University Medical Center Utrecht, The Netherlands (O.I.W., G.T.S., F.M.).
⁷ German Heart Center Berlin, Department of Congenital Heart Disease, Pediatric Cardiology, DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany (F.B., S.S.).
⁸ Population Health Sciences Institute, Newcastle University, Newcastle, United Kingdom (H.J.C.).
⁹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, UTHealth School of Public Health, Houston, TX (A.J.A.).
¹⁰ Heart Centre for Children, The Children's Hospital at Westmead and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Australia (G.M.B., D.S.W.).
¹¹ Department of Clinical Genetics, Leiden University Medical Center, The Netherlands (D.Q.C.M.B.-S.).
¹² University of Leuven, Belgium (M.G.).
¹³ Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Québec, Canada (C.P., G.A.).
¹⁴ The Jackson Laboratory, Bar Harbor, ME (C.P.).
¹⁵ Division of Pediatric Cardiology, Department of Pediatrics (R.B., R.L.F.v.d.P.), Leiden University Medical Center, The Netherlands.
¹⁶ Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany (M.M.-N.).
¹⁷ IBE, Faculty of Medicine, LMU Munich, Germany (M.M.-N.).
¹⁸ Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.M.-N.).
¹⁹ Department of Cardiology (H.W.V.), Leiden University Medical Center, The Netherlands.
²⁰ Department of Cardiology, Amsterdam University Medical Centers, VU Amsterdam, The Netherlands (T.C.K.).
²¹ Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.P.v.M.).
²² Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands (A.P.J.v.D., R.R.J.v.K.).
²³ Department of Cardiology, Maastricht University Medical Center, The Netherlands (R.R.J.v.K.).
²⁴ Department of Cardiology, Erasmus Medical Center, Erasmus University, Rotterdam, The Netherlands (J.W.R.-H.).
²⁵ Saarland University Medical Center, Department of Pediatric Cardiology, Homburg, Germany (H.A.-K.).
²⁶ Unité Médico-Chirurgicale de Cardiologie Congénitale et Pédiatrique, Centre de référence Malformations Cardiaques Congénitales Complexes - M3C, Hôpital Necker Enfants Malades, APHP and Université Paris Descartes, Sorbonne Paris Cité, Paris, France (F.B., D.B.).
²⁷ Charité, Universitätsmedizin Berlin, Department for Paediatric Cardiology, Germany (F.B.).
²⁸ Department of Pediatric Cardiology, Friedrich-Alexander-University of Erlangen-Nuernberg (FAU), Germany (S.D., J.M.).
²⁹ Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein/Campus Kiel, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (M.-P.H.).
³⁰ Department of Human Genetics, University Medical Center Schleswig-Holstein, Kiel, Germany (M.-P.H.).
³¹ Leipzig Heart Center, Department of Pediatric Cardiology, University of Leipzig, Germany (F.-T.R.).
³² Heart and Diabetes Center NRW, Center of Congenital Heart Disease, Ruhr-University of Bochum, Bad Oeynhausen, Germany (S.S.).
³³ Sorbonne Paris Nord (Paris 13) University, Inserm U1153, Inrae U1125, Cnam, Nutritional Epidemiology Research Team (EREN), Epidemiology and Statistics Research Center - University of Paris (CRESS), Bobigny, France (P.G.).
³⁴ McGill Genome Centre and Department of Human Genetics, McGill University, Montreal, Québec, Canada (M.L., H.M.M.).
³⁵ Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King's College London, United Kingdom (A.A.-C.).
³⁶ United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom (C.E.S.).
³⁷ Centre for Brain Research, University of Auckland, New Zealand (C.E.S.).
³⁸ Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield and NIHR Sheffield Biomedical Research Centre for Translational Neuroscience, United Kingdom (P.J.S.).
³⁹ Faculty of Medicine Health & Life Sciences, Queens University Belfast, United Kingdom (K.E.M.).
⁴⁰ Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands (J.H.V., L.H.v.d.B.).
⁴¹ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego (S.E.).
⁴² Department of Human Genetics, University of Chicago, IL (M.A.N., I.A.).
⁴³ Helmholtz Zentrum Munich, Institut of Human Genetics, Neuherberg, Germany (M.R.-B., T.M.).
⁴⁴ Division of Cardiology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada (T.M.).
⁴⁵ Peter Munk Cardiac Center, Toronto Congenital Cardiac Centre for Adults and University of Toronto, Canada (E.O.).
⁴⁶ DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (T.M.).
⁴⁷ Division of Cardiology, Department of Medicine, London Health Sciences Centre, ON, Canada (L.B.).
⁴⁸ Division of Cardiology, Department of Pediatrics, Kingston General Hospital, ON, Canada (J.F.S.).
⁴⁹ Western University, Ontario, Canada (L.A.-D.).
⁵⁰ Division of Cardiology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada (J.L.).
⁵¹ Department of Epidemiology, Mailman School of Public Health, Columbia University, NY (J.K.).
⁵² Clinical Genetics Research Program, Centre for Addiction and Mental Health (A.S.B.).
⁵³ Department of Psychiatry, University of Toronto, Toronto General Hospital, University Health Network, Ontario, Canada (A.S.B.).
⁵⁴ CPDPN, Hôpital MFME, CHU Martinique, Fort de France, Martinique, France (P.B.).
⁵⁵ Department of Pediatric Cardiology, Emma Children's Hospital Amsterdam University Medical Centers (AMC), The Netherlands (S.-A.B.C.).
⁵⁶ Centre for Congenital Heart Disease Amsterdam-Leiden (CAHAL) (S.-A.B.C.).
⁵⁷ Center for Human Genetics University Hospitals KU Leuven, Belgium (J.B.).
⁵⁸ Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, The Netherlands (W.S.K.-F.).
⁵⁹ National Register for Congenital Heart Defects, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (U.M.M.B.).
⁶⁰ Hospital for Sick Children, University of Toronto, Ontario, Canada (S.M.).
⁶¹ Division of Cardiology, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (E.G.).
⁶² Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester and Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, United Kingdom (B.K.).
⁶³ Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health (APH), Amsterdam University Medical Centers, University of Amsterdam, The Netherlands (M.W.T.T.).
⁶⁴ Division of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, the Netherlands (J.B.).

^# Contributed equally.

PMID: 34886679
PMCID: PMC8768504
DOI: 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.

Keywords: Wnt-5a protein; congenital heart disease; genome-wide association study; single nucleotide polymorphism; transposition of great vessels.

PubMed Disclaimer

Figures

**Figure 1.**
**Manhattan plots of the genome-wide association results.** P of all tested single nucleotide polymorphisms (SNPs) on a –log10 scale from the logistic regression analysis in the discovery set including 1094 cases and 3282 controls (A) and the meta-analysis of the discovery and replication set including 1237 cases and 3711 controls (B). Dashed lines represent genome-wide significance P thresholds of 5×10⁻⁸. C, Regional association plot of the 3p14.3 locus and surrounding genes (±500 kb). The y-axis represent the −log10(P) values from the meta-analysis. Round points represent SNPs in this region, colored by degree of linkage disequilibrium with rs56219800, the top associated SNP (purple point). The blue highlighted region represents the size of the locus, as defined by all SNPs with an r²≥0.5 with the lead SNP and that showed an association P of <10⁻³.

**Figure 2.**
**Functional annotation of the 3p14.3 locus.** From top to bottom: Hi-C data from the human lymphobastoid line GM12878; TADs derived from iPSC-CMs; RefSeq genes; results from the TGA genome-wide association studies meta-analysis on a –log10(P) scale; human EMERGE track; Genomic Evolutionary Rate Profiling (GERP) conservation track. The blue highlighted region represents the genome-wide associated 3p14.3 locus near *WNT5A*.

**Figure 3.**
**Characterization of RE1 in mouse and zebrafish.** A, Genome browser view from the mouse orthologous *Wnt5a* genomic region. ChIP-seq tracks of TBX20 and H3K27Ac are displayed below. B, Representative embryos showing that RE1-lacZ reporter expression is observed in the developing murine heart, including outflow tract myocardium and ventricles. In total, 5 embryos were analyzed. A, atrium; V, ventricle; OFT, outflow tract. C, Representative image of 2dpf zebrafish showing RE1 activity in various organs and tissues, including the heart. In total, 296 embryos were analyzed. White dashed lines represent boundaries of ventricle and atrium. v: ventricle; a: atrium. D, TBX20 ChIP-Seq demonstrating RE1 to be bound by TBX20. E, Expression levels (average normalized read counts and SD) of *Wnt5a* and flanking genes in E11.5 FACS sorted cardiomyocytes from control (n=4) and cTnT-Cre;*Tbx20* mutant murine hearts (n=4), *P=0.04, using limma adjusted for multiple testing using Benjamini-Hochberg correction.

**Figure 4.**
**Regulatory activity of RE1 for the 3 major human haplotypes in vitro.** A, Genome browser view from the human RE1 region (ie, chr3:55,605,229-55,607,027; GRCh37), depicting the location and characteristics of the single nucleotide polymorphisms (SNPs) within RE1 and the 3 major haplotypes. Provided r² and D-prime are in relationship to the lead SNP rs56219800. B, Luciferase activity were measured in HL1 cells transfected with constructs for RE1 haplotype 1 (n=4), haplotype 2 (n=8), and haplotype 3 (n=4). Values were normalized to the activity of empty pGL4-SCP1-luc. *P=2.6×10⁻⁵, **P=2.6×10⁻⁶ (1-way ANOVA). C, TBX20 motif sequence as identified by HOMER motif analysis showing rs79492708 abolishes a TBX20-binding site.

See this image and copyright information in PMC

Comment in

Human 3p14.3: A Regulatory Region in Transposition of the Great Arteries.
Cashman TJ, Trivedi CM. Cashman TJ, et al. Circ Res. 2022 Jan 21;130(2):181-183. doi: 10.1161/CIRCRESAHA.121.320624. Epub 2022 Jan 20. Circ Res. 2022. PMID: 35050689 Free PMC article. No abstract available.

References

1. Martins P, Castela E. Transposition of the great arteries. Orphanet J Rare Dis. 2008;3:27. doi: 10.1186/1750-1172-3-27 - PMC - PubMed
1. van der Bom T, Bouma BJ, Meijboom FJ, Zwinderman AH, Mulder BJ. The prevalence of adult congenital heart disease, results from a systematic review and evidence based calculation. Am Heart J. 2012;164:568–575. doi: 10.1016/j.ahj.2012.07.023 - PubMed
1. Williams WG, McCrindle BW, Ashburn DA, Jonas RA, Mavroudis C, Blackstone EH; Congenital Heart Surgeon’s Society. Outcomes of 829 neonates with complete transposition of the great arteries 12-17 years after repair. Eur J Cardiothorac Surg. 2003;24:1–9. discussion 9. doi: 10.1016/s1010-7940(03)00264-1 - PubMed
1. Zomer AC, Bouma BJ, Mulder BJ, van der Bom T, Carla Zomer A, Zwinderman AH, Meijboom FJ, Bouma BJ, Mulder BJ. The changing epidemiology of congenital heart disease. Nat Rev Cardiol. 2010;8:50–60. doi:10.1038/nrcardio.2010.166 - PubMed
1. Mégarbané A, Salem N, Stephan E, Ashoush R, Lenoir D, Delague V, Kassab R, Loiselet J, Bouvagnet P. X-linked transposition of the great arteries and incomplete penetrance among males with a nonsense mutation in ZIC3. Eur J Hum Genet. 2000;8:704–708. doi: 10.1038/sj.ejhg.5200526 - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources