Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

Sophie Garnier; Magdalena Harakalova; Stefan Weiss; Michal Mokry; Vera Regitz-Zagrosek; Christian Hengstenberg; Thomas Cappola; Richard Isnard; Eloisa Arbustini; Stuart Cook; Jessica van Setten; Jorg Calis; Hakon Hakonarson; Michael Morley; Klaus Stark; Sanjay Prasad; Jin Li; Declan O'Regan; Maurizia Grasso; Martina Müller-Nurasyid; Thomas Meitinger; Jean-Philippe Empana; Konstantin Strauch; Melanie Waldenberger; Kenneth Marguiles; Christine Seidman; Georgios Kararigas; Benjamin Meder; Jan Haas; Pierre Boutouyrie; Patrick Lacolley; Xavier Jouven; Jeanette Erdmann; Stefan Blankenberg; Thomas Wichter; Volker Ruppert; Luigi Tavazzi; Olivier Dubourg; Gérard Roizes; Richard Dorent; Pascal de Groote; Laurent Fauchier; Jean-Noël Trochu; Jean-François Aupetit; Zofia Bilinska; Marine Germain; Uwe Völker; Daiane Hemerich; Ibticem Raji; Delphine Bacq-Daian; Carole Proust; Paloma Remior; Manuel Gomez-Bueno; Kristin Lehnert; Renee Maas; Robert Olaso; Ganapathi Varma Saripella; Stephan Felix; Steven Mcginn; Laëtitia Duboscq-Bidot; Alain van Mil; Céline Besse; Vincent Fontaine; Hélène Blanché; Flavie Ader; Brendan Keating; Angélique Curjol; Anne Boland; Michel Komajda; François Cambien; Jean-François Deleuze; Marcus Dörr; Folkert Asselbergs; Eric Villard; David-Alexandre Trégouët; Philippe Charron

doi:10.1093/eurheartj/ehab030

Article de revue

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

Sophie Garnier, Magdalena Harakalova, Stefan Weiss, Michal Mokry, Vera Regitz-Zagrosek, Christian Hengstenberg, Thomas Cappola, Richard Isnard, Eloisa Arbustini, Stuart Cook, …

European Heart Journal, Vol.42(20), pp.2000-2011

21/05/2021

DOI: https://doi.org/10.1093/eurheartj/ehab030

PMCID: PMC8139853

PMID: 33677556

Résumé

Dilated cardiomyopathy

Imputation

Heart failure

Genetic risk score

GWAS

4C-sequencing

Dilated cardiomyopathy

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.

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Titre: Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23
Créateurs - sans rôle: Sophie Garnier - Inserm
Magdalena Harakalova - Utrecht University
Stefan Weiss - Universität Greifswald
Michal Mokry - Heidelberg University
Vera Regitz-Zagrosek - Charité - Universitätsmedizin Berlin
Christian Hengstenberg - Medical University of Vienna
Thomas Cappola - University of Pennsylvania
Richard Isnard - Unité de recherche sur les maladies cardiovasculaires et métaboliques
Eloisa Arbustini - Policlinico San Matteo Fondazione
Stuart Cook - Duke-NUS Medical School
Jessica van Setten - University Medical Center Utrecht
Jorg Calis - University Medical Center [Utrecht]
Hakon Hakonarson - Children's Hospital of Philadelphia
Michael Morley - University of Pennsylvania
Klaus Stark - University of Regensburg
Sanjay Prasad - National Heart Centre Singapore
Jin Li - Children's Hospital of Philadelphia
Declan O'Regan - Imperial College London
Maurizia Grasso - Policlinico San Matteo Fondazione
Martina Müller-Nurasyid - Helmholtz Zentrum München
Thomas Meitinger - Helmholtz Zentrum München
Jean-Philippe Empana - Unité de recherche sur les maladies cardiovasculaires et métaboliques
Konstantin Strauch - University Medical Center of the Johannes Gutenberg University Mainz
Melanie Waldenberger - Helmholtz Zentrum München
Kenneth Marguiles - University of Pennsylvania
Christine Seidman - Harvard University
Georgios Kararigas - University of Iceland
Benjamin Meder - Heidelberg University
Jan Haas - Heidelberg University
Pierre Boutouyrie - Hôpital Européen Georges-Pompidou
Patrick Lacolley - Centre de Médecine Préventive
Xavier Jouven - Inserm
Jeanette Erdmann - Johannes Gutenberg University Mainz
Stefan Blankenberg - University of Lübeck
Thomas Wichter - Marienhospital Osnabrück
Volker Ruppert - Universitätklinikum Gießen und Marburg GmbH
Luigi Tavazzi - Maria Cecilia Hospital
Olivier Dubourg - Assistance Publique – Hôpitaux de Paris
Gérard Roizes - Université de Montpellier, Institut de Génétique Humaine - IGH
Richard Dorent - Hôpital Tenon
Pascal de Groote - Lille’s Cardiology Hospital
Laurent Fauchier - Centre Hospitalier Universitaire de Tours
Jean-Noël Trochu - Institut du Thorax
Jean-François Aupetit - Centre Hospitalier Saint-Joseph Saint-Luc
Zofia Bilinska - Institute of Cardiology
Marine Germain - Université de Bordeaux
Uwe Völker - German Centre for Cardiovascular Research
Daiane Hemerich - University Medical Center Utrecht
Ibticem Raji - Assistance Publique – Hôpitaux de Paris
Delphine Bacq-Daian - Université Paris-Saclay
Carole Proust - Bordeaux Population Health
Paloma Remior - Centro de Investigación en Red en Enfermedades Cardiovasculares
Manuel Gomez-Bueno - Centro de Investigación en Red en Enfermedades Cardiovasculares
Kristin Lehnert - Universitätsmedizin Greifswald
Renee Maas - University Medical Center [Utrecht]
Robert Olaso - Centre National de Recherche en Génomique Humaine
Ganapathi Varma Saripella - Sorbonne Université
Stephan Felix - Universitätsmedizin Greifswald
Steven Mcginn - Centre National de Recherche en Génomique Humaine
Laëtitia Duboscq-Bidot - Sorbonne Université
Alain van Mil - University Medical Center Utrecht
Céline Besse - Université Paris-Saclay
Vincent Fontaine - Sorbonne Université
Hélène Blanché - Genomics Medicine
Flavie Ader - Sorbonne Université
Brendan Keating - University of Pennsylvania
Angélique Curjol - Sorbonne Université
Anne Boland - Genomics Medicine
Michel Komajda - Fondation pour l’innovation en Cadiométabolisme et Nutrition
François Cambien - Université de Bordeaux
Jean-François Deleuze - Centre National de Recherche en Génomique Humaine
Marcus Dörr - German Centre for Cardiovascular Research
Folkert Asselbergs - Health Data Research UK
Eric Villard - Inserm
David-Alexandre Trégouët - Bordeaux Population Health
Philippe Charron - Sorbonne Université
Détails de publication: European Heart Journal, Vol.42(20), pp.2000-2011
Note de subvention: Assistance publique-Hôpitaux de Paris
Identifiants: 99161875609311
Unité académique: Institut de Génétique Humaine - IGH
Langue: English
Type de ressource: Journal article
Champs locaux: hal-03567179