Sophie Garnier1,2, Magdalena Harakalova3,4, Stefan Weiss5,6, Michal Mokry3,7,8, Vera Regitz-Zagrosek9,10, Christian Hengstenberg11,12, Thomas P Cappola13, Richard Isnard1,2,14, Eloisa Arbustini15, Stuart A Cook16,17,18, Jessica van Setten3, Jorg J A Calis3,4, Hakon Hakonarson19, Michael P Morley13, Klaus Stark20, Sanjay K Prasad17,21, Jin Li19, Declan P O'Regan22, Maurizia Grasso23, Martina Müller-Nurasyid24,25,26, Thomas Meitinger24,25,27, Jean-Philippe Empana28, Konstantin Strauch24,25,29, Melanie Waldenberger30,31, Kenneth B Marguiles13, Christine E Seidman32,33, Georgios Kararigas34, Benjamin Meder35,36, Jan Haas35, Pierre Boutouyrie28,37, Patrick Lacolley38, Xavier Jouven28,37, Jeanette Erdmann39, Stefan Blankenberg40, Thomas Wichter41, Volker Ruppert42, Luigi Tavazzi43, Olivier Dubourg44, Gérard Roizes45, Richard Dorent46, Pascal de Groote47, Laurent Fauchier48, Jean-Noël Trochu49, Jean-François Aupetit50, Zofia T Bilinska51, Marine Germain52, Uwe Völker5,6, Daiane Hemerich3, Ibticem Raji53, Delphine Bacq-Daian54,55, Carole Proust52, Paloma Remior56, Manuel Gomez-Bueno56, Kristin Lehnert6,57, Renee Maas3,4, Robert Olaso54,55, Ganapathi Varma Saripella1,58, Stephan B Felix6,57, Steven McGinn54,55, Laëtitia Duboscq-Bidot1,2, Alain van Mil3,4, Céline Besse54,55, Vincent Fontaine1,2, Hélène Blanché55,59, Flavie Ader1,60,61, Brendan Keating62, Angélique Curjol53, Anne Boland54,55, Michel Komajda1,2,63, François Cambien52, Jean-François Deleuze54,55,59, Marcus Dörr6,57, Folkert W Asselbergs3,64,65, Eric Villard1,2, David-Alexandre Trégouët52,55, Philippe Charron1,2,14,53. 1. Sorbonne Université, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris 75013, France. 2. ICAN Institute for Cardiometabolism and Nutrition, Paris 75013, France. 3. Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. 4. Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands. 5. Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany. 6. DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. 7. Laboratory of Clinical Chemistry and Haematology, University Medical Center, Heidelberglaan 100, Utrecht, the Netherlands. 8. Laboratory of Experimental Cardiology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, the Netherlands. 9. Institute of Gender in Medicine and Center for Cardiovascular Research, Charite University Hospital, Berlin, Germany. 10. DZHK (German Center for Cardiovascular Research), Berlin, Germany. 11. Department of Internal Medicine, Division of Cardiology, Medical University of Vienna, Austria. 12. Department of Internal Medicine, Medical University of Regensburg, Germany. 13. Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 14. Cardiology Department, APHP, Pitié-Salpêtrière Hospital, Paris, France. 15. IRCCS Fondazione Policlinico San Matteo, Pavia, Italy. 16. National Heart and Lung Institute, Imperial College London, London, UK. 17. National Heart Centre Singapore, Singapore. 18. Duke-NUS, Singapore. 19. Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 20. Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany. 21. Royal Brompton Hospital, London, UK. 22. Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. 23. Centre for Inherited Cardiovascular Diseases-IRCCS Fondazione Policlinico San Matteo, Pavia, Italy. 24. Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. 25. IBE, Faculty of Medicine, LMU Munich, Germany. 26. Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany. 27. Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. 28. Université de Paris, INSERM, UMR-S970, Integrative Epidemiology of cardiovascular disease, Paris, France. 29. Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz 55101, Germany. 30. Research unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. 31. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. 32. Department of Medicine and Genetics Harvard Medical School, Boston, MA, USA. 33. Brigham & Women's Cardiovascular Genetics Center, Boston, MA, USA. 34. Department of Physiology, Faculty of Medicine, University of Iceland, Vatnsmýrarvegur 16, 101 Reykjavík, Iceland. 35. Institute for Cardiomyopathies Heidelberg, Heidelberg University, Germany. 36. Stanford Genome Technology Center, Department of Genetics, Stanford Medical School, CA, USA. 37. Cardiology Department, APHP, Georges Pompidou European Hospital, Paris, France. 38. INSERM U1116, Faculté de Médecine, Vandoeuvre-les-Nancy, France. 39. Medizinische Klinik und Poliklinik, Universitätsmedizin der Johannes-Gutenberg Universität Mainz, Mainz, Germany. 40. Medizinische Klinik II, Universität Lübeck, Lübeck, Germany. 41. Dept. of Cardiology and Angiology, Niels-Stensen-Kliniken Marienhospital Osnabrück, Heart Centre Osnabrück/Bad Rothenfelde, Osnabrück 49074, Germany. 42. Klinik für Innere Medizin-Kardiologie UKGM GmbH Standort Marburg Baldingerstrasse, Marburg, Germany. 43. Maria Cecilia Hospital, GVM Care and Research, Cotignola, Italy. 44. Université de Versailles-Saint Quentin, Hôpital Ambroise Paré, AP-HP, Boulogne, France. 45. Institut de Génétique Humaine, UPR 1142, CNRS, Montpellier, France. 46. Service de Cardiologie, CHU Tenon, Paris, France. 47. Service de Cardiologie, Hôpital Cardiologique, Lille, France. 48. Service de Cardiologie, Centre Hospitalier Universitaire Trousseau, Tours, France. 49. Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes 44000, France. 50. Département de pathologie cardiovasculaire, Hôpital Saint-Joseph-Saint-Luc, Lyon, France. 51. Unit for Screening Studies in Inherited Cardiovascular Diseases, National Institute of Cardiology, Warsaw, Poland. 52. Univ. Bordeaux, INSERM, BPH, U1219, Bordeaux 33000, France. 53. AP-HP, Département de Génétique, Centre de Référence Maladies Cardiaques Héréditaires, Hôpital Pitié-Salpêtrière, Paris, France. 54. Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry 91057, France. 55. Laboratory of Excellence GENMED (Medical Genomics). 56. Department of Cardiology, Hospital Universitario Puerta de Hierro, CIBERCV, Madrid, Spain. 57. Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany. 58. SLU Bioinformatics Infrastructure (SLUBI), PlantLink, Department of Plant Breeding, Swedish University of Agricultural Sciences, Almas Allé 8, 750 07 Uppsala, Sweden. 59. Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, Paris, France. 60. APHP, UF Cardiogénétique et Myogénétique, service de Biochimie métabolique, Hôpital universitaire Pitié-Salpêtrière Paris, France. 61. Faculté de Pharmacie Paris Descartes, Département 3, Paris 75006, France. 62. Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA. 63. Cardiology Department, Groupe Hospitalier Paris Saint Joseph, Paris, France. 64. Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK. 65. Health Data Research UK and Institute of Health Informatics, University College London, London, UK.
Abstract
AIMS: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. METHODS AND RESULTS: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. CONCLUSION: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. METHODS AND RESULTS: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. CONCLUSION: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Magdalena Harakalova; Gijs Kummeling; Arjan Sammani; Marijke Linschoten; Annette F Baas; Jasper van der Smagt; Pieter A Doevendans; J Peter van Tintelen; Dennis Dooijes; Michal Mokry; Folkert W Asselbergs Journal: Eur J Heart Fail Date: 2015-03-02 Impact factor: 15.534
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Authors: Mathieu Lemire; Syed H E Zaidi; Maria Ban; Bing Ge; Dylan Aïssi; Marine Germain; Irfahan Kassam; Mike Wang; Brent W Zanke; France Gagnon; Pierre-Emmanuel Morange; David-Alexandre Trégouët; Philip S Wells; Stephen Sawcer; Steven Gallinger; Tomi Pastinen; Thomas J Hudson Journal: Nat Commun Date: 2015-02-26 Impact factor: 14.919
Authors: Huichun Xu; Gerald W Dorn; Amol Shetty; Ankita Parihar; Tushar Dave; Shawn W Robinson; Stephen S Gottlieb; Mark P Donahue; Gordon F Tomaselli; William E Kraus; Braxton D Mitchell; Stephen B Liggett Journal: J Pers Med Date: 2018-02-26
Authors: Jie Zheng; A Mesut Erzurumluoglu; Benjamin L Elsworth; John P Kemp; Laurence Howe; Philip C Haycock; Gibran Hemani; Katherine Tansey; Charles Laurin; Beate St Pourcain; Nicole M Warrington; Hilary K Finucane; Alkes L Price; Brendan K Bulik-Sullivan; Verneri Anttila; Lavinia Paternoster; Tom R Gaunt; David M Evans; Benjamin M Neale Journal: Bioinformatics Date: 2016-09-22 Impact factor: 6.937
Authors: James P Pirruccello; Alexander Bick; Minxian Wang; Mark Chaffin; Samuel Friedman; Jie Yao; Xiuqing Guo; Bharath Ambale Venkatesh; Kent D Taylor; Wendy S Post; Stephen Rich; Joao A C Lima; Jerome I Rotter; Anthony Philippakis; Steven A Lubitz; Patrick T Ellinor; Amit V Khera; Sekar Kathiresan; Krishna G Aragam Journal: Nat Commun Date: 2020-05-07 Impact factor: 17.694
Authors: Matthias Heinig; Michiel E Adriaens; Sebastian Schafer; Hanneke W M van Deutekom; Elisabeth M Lodder; James S Ware; Valentin Schneider; Leanne E Felkin; Esther E Creemers; Benjamin Meder; Hugo A Katus; Frank Rühle; Monika Stoll; François Cambien; Eric Villard; Philippe Charron; Andras Varro; Nanette H Bishopric; Alfred L George; Cristobal Dos Remedios; Aida Moreno-Moral; Francesco Pesce; Anja Bauerfeind; Franz Rüschendorf; Carola Rintisch; Enrico Petretto; Paul J Barton; Stuart A Cook; Yigal M Pinto; Connie R Bezzina; Norbert Hubner Journal: Genome Biol Date: 2017-09-14 Impact factor: 13.583
Authors: Yunju Yang; Traci M Bartz; Michael R Brown; Xiuqing Guo; Nuno R Zilhão; Stella Trompet; Stefan Weiss; Jie Yao; Jennifer A Brody; Christopher R Defilippi; Ron C Hoogeveen; Henry J Lin; Vilmundur Gudnason; Christie M Ballantyne; Marcus Dörr; J Wouter Jukema; Astrid Petersmann; Bruce M Psaty; Jerome I Rotter; Eric Boerwinkle; Myriam Fornage; Goo Jun; Bing Yu Journal: Circ Genom Precis Med Date: 2021-11-04
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Back Sternick Eduardo; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong-Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti Mac Intyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Pablo Ochoa Juan; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: J Arrhythm Date: 2022-05-31
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Eduardo Back Sternick; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti MacIntyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Juan Pablo Ochoa; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: Europace Date: 2022-09-01 Impact factor: 5.486
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Authors: Rudolf A de Boer; Stephane Heymans; Johannes Backs; Lucie Carrier; Andrew J S Coats; Stefanie Dimmeler; Thomas Eschenhagen; Gerasimos Filippatos; Lior Gepstein; Jean-Sebastien Hulot; Ralph Knöll; Christian Kupatt; Wolfgang A Linke; Christine E Seidman; C Gabriele Tocchetti; Jolanda van der Velden; Roddy Walsh; Petar M Seferovic; Thomas Thum Journal: Eur J Heart Fail Date: 2022-01-14 Impact factor: 17.349