Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries-Reference-Cited by-同舟云学术

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

Published:2022-01-21 Issue:2 Volume:130 Page:166-180
ISSN:0009-7330
Container-title:Circulation Research
language:en
Short-container-title:Circ Res

Author:

Škorić-Milosavljević Doris¹²^ORCID,Tadros Rafik¹³^ORCID,Bosada Fernanda M.⁴^ORCID,Tessadori Federico⁵^ORCID,van Weerd Jan Hendrik⁴^ORCID,Woudstra Odilia I.¹⁶^ORCID,Tjong Fleur V.Y.¹^ORCID,Lahrouchi Najim¹^ORCID,Bajolle Fanny⁷^ORCID,Cordell Heather J.⁸^ORCID,Agopian A.J.⁹^ORCID,Blue Gillian M.¹⁰^ORCID,Barge-Schaapveld Daniela Q.C.M.¹¹^ORCID,Gewillig Marc¹²^ORCID,Preuss Christoph¹³¹⁴^ORCID,Lodder Elisabeth M.¹²^ORCID,Barnett Phil⁴^ORCID,Ilgun Aho⁴,Beekman Leander¹,van Duijvenboden Karel⁴,Bokenkamp Regina¹⁵,Müller-Nurasyid Martina¹⁶¹⁷¹⁸^ORCID,Vliegen Hubert W.¹⁹^ORCID,Konings Thelma C.²⁰,van Melle Joost P.²¹,van Dijk Arie P.J.²²,van Kimmenade Roland R.J.²²²³,Roos-Hesselink Jolien W.²⁴^ORCID,Sieswerda Gertjan T.⁶^ORCID,Meijboom Folkert⁶,Abdul-Khaliq Hashim²⁵^ORCID,Berger Felix²⁶²⁷^ORCID,Dittrich Sven²⁸^ORCID,Hitz Marc-Phillip²⁹³⁰,Moosmann Julia²⁸^ORCID,Riede Frank-Thomas³¹,Schubert Stephan⁷³²^ORCID,Galan Pilar³³,Lathrop Mark³⁴^ORCID,Munter Hans M.³⁴,Al-Chalabi Ammar³⁵^ORCID,Shaw Christopher E.³⁶³⁷^ORCID,Shaw Pamela J.³⁸^ORCID,Morrison Karen E.³⁹^ORCID,Veldink Jan H.⁴⁰^ORCID,van den Berg Leonard H.⁴⁰,Evans Sylvia⁴¹^ORCID,Nobrega Marcelo A.⁴²^ORCID,Aneas Ivy⁴²,Radivojkov-Blagojević Milena⁴³^ORCID,Meitinger Thomas⁴³⁴⁴^ORCID,Oechslin Erwin⁴⁵^ORCID,Mondal Tapas⁴⁶,Bergin Lynn⁴⁷^ORCID,Smythe John F.⁴⁸,Altamirano-Diaz Luis⁴⁹^ORCID,Lougheed Jane⁵⁰^ORCID,Bouma Berto J.¹^ORCID,Chaix Marie-A.³^ORCID,Kline Jennie⁵¹,Bassett Anne S.⁵²⁵³^ORCID,Andelfinger Gregor¹³^ORCID,van der Palen Roel L.F.¹⁵^ORCID,Bouvagnet Patrice⁵⁴^ORCID,Clur Sally-Ann B.⁵⁵⁵⁶^ORCID,Breckpot Jeroen⁵⁵⁷^ORCID,Kerstjens-Frederikse Wilhelmina S.⁵⁸^ORCID,Winlaw David S.¹⁰^ORCID,Bauer Ulrike M.M.⁵⁹^ORCID,Mital Seema⁶⁰^ORCID,Goldmuntz Elizabeth⁶¹^ORCID,Keavney Bernard⁶²^ORCID,Bonnet Damien²⁶^ORCID,Mulder Barbara J.¹,Tanck Michael W.T.⁶³^ORCID,Bakkers Jeroen⁶⁴^ORCID,Christoffels Vincent M.⁴^ORCID,Boogerd Cornelis J.⁵^ORCID,Postma Alex V.²⁴^ORCID,Bezzina Connie R.¹^ORCID,

Affiliation:

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.).

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.

Funder

Hartstichting

Fondation Leducq

Children's Heart Foundation

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

Link

https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.120.317107

Reference103 articles.

1. Transposition of the great arteries